Molecules derived from the extremes of life

Contents

• 1 Introduction
  • 1.1 Brief history of the discovery of extremophiles
  • 1.2 Classification of microorganisms found in extreme environments
  • 1.3 Scope of this review

• 2 High temperature
  • 2.1 Secondary metabolites
  • 2.2 Polyamines
  • 2.3 Nucleosides
  • 2.4 Osmolytes
  • 2.5 Carbohydrates
  • 2.6 Lipids

• 3 Low temperature
  • 3.1 Secondary metabolites

• 4 High pressure
  • 4.1 Secondary metabolites
  • 4.2 Carbohydrates

• 5 High salt
  • 5.1 Secondary metabolites
  • 5.2 Polyamines
  • 5.3 Nucleosides
  • 5.4 Osmolytes
  • 5.5 Carbohydrates
  • 5.6 Lipids

• 6 High pH
  • 6.1 Secondary metabolites
  • 6.2 Carbohydrates
  • 6.3 Lipids

• 7 Low pH
  • 7.1 Secondary metabolites
  • 7.2 Carbohydrates
  • 7.3 Lipids

• 8 Conclusions

• References

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Abstract

Covering: up to early 2008

In order to survive extremes of pH, temperature, salinity and pressure, organisms have been found to develop unique defences against their environment, leading to the biosynthesis of novel molecules ranging from simple osmolytes and lipids to complex secondary metabolites. This review highlights novel molecules isolated from microorganisms that either tolerate or favour extreme growth conditions.

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Zoe E. Wilson

Zoe Wilson grew up in Warkworth, New Zealand, before moving to Auckland to attend the University of Auckland where she completed a BSc in 2005 and a BSc (Hons) in Medicinal Chemistry under the supervision of Professor Margaret Brimble in 2006. She is currently undertaking a PhD with Professor Brimble on the total synthesis of the extremophile natural product berkelic acid.

Margaret A. Brimble

Margaret Brimble was born in Auckland, New Zealand, where she was educated and graduated from the University of Auckland with an MSc (1^st class) in chemistry. She was then awarded a UK Commonwealth Scholarship to undertake her PhD studies at Southampton University. In 1986 she was appointed as a lecturer at Massey University, NZ. After a brief stint as a visiting Professor at the University of California, Berkeley, she moved to the University of Sydney where she was promoted to Reader. In 1999, she returned to New Zealand to take up the Chair in Organic and Medicinal Chemistry at the University of Auckland, where her research program continues to focus on the synthesis of spiroacetal-containing natural products (especially shellfish toxins), the synthesis of pyranonaphthoquinone antibiotics, the synthesis of alkaloids and peptidomimetics for the treatment of neurodegenerative disorders, and the synthesis of glycopeptides as components for cancer vaccines. She is currently President-Elect of the International Society of Heterocyclic Chemistry and was named the 2007 L'Oréal–UNESCO For Women in Science Laureate for Asia–Pacific in Materials Science.

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1 Introduction

1.1 Brief history of the discovery of extremophiles

A microorganism is classified as an extremophile if it grows optimally under conditions outside that which would have traditionally been considered life-supporting. Extreme-tolerant microorganisms in comparison can survive these harsh conditions, but grow best under more moderate conditions.

Although the first extremophilic organism, which was thermophilic (heat-loving), was isolated in the 1860's, it was over a century later that it began to be widely accepted that there were a significant number of organisms capable of surviving in extreme environments, leading to a rapid growth in research in this area.¹ The term “extremophile” as a broad grouping for organisms which live optimally under extreme conditions was first proposed by MacElroy in 1974.²

Investigation of extreme environments led to the discovery of a novel group of microorganisms which were named archaeabacteria due to their primitive structures. These microorganisms were distinct from prokaryotes and eukaryotes on a molecular level, which led to Woese revising the natural taxonomy of life such that all living things were divided into one of three domains – the eucarya, the bacteria and the archaea.³ Originally it was thought that all archaea were extremophilic, but further studies have shown that there are in fact archaea which inhabit milder climates.⁴ It has been found that all three domains contain some examples of extremophilic organisms, though to date the most extreme conditions are inhabited by archaea. Reviews have been published which discuss extremophile isolation as well as some of the mechanisms which have been developed to combat the environments which these microorganisms inhabit.^1,5,6

1.2 Classification of microorganisms found in extreme environments

Traditionally, the extremes of life are considered to be high and low temperature, high pressure, high and low pH, and high salt. More recently some organisms have been classed as extremophiles for being able to tolerate radiation or high concentrations of heavy metals, but as these organisms usually grow equally well if not better in the absence of these stresses they can not be considered to be true extremophiles.⁷

Many extremophilic organisms isolated to date actually thrive in environments which are extreme in two or more aspects, for example Thermoplasma acidophilum, a thermoacidophile, which grows optimally at 59 °C and pH 1.0–2.0.⁸ The thresholds for what is considered to be extremophilic varies between publications. A good discussion of the problems inherent in the classification of an organism as extremophilic is included in the 2001 review by Rothschild and Mancinelli.⁵

For the purpose of the present review the conditions in Table 1 were used to guide classification, with microorganisms only being termed extremophilic if their optimal growth falls within these ranges.

Table 1 Classification of extremophiles

Extremophile	Environmental factor	Optimum growth conditions
Thermophile	High temperature	50–60 °C (moderate thermophile)
		61–79 °C (thermophile)
		>80 °C (hyperthermophile)
Psychrophile	Low temperature	<20 °C
Piezophile (barophile)	High pressure	>35 MPa (1 m depth = 10.5 kPa)
Halophile	High salt	>3% NaCl
Alkaliphile	High pH	pH >9
Acidophile	Low pH	pH <4

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1.3 Scope of this review

This review will focus on the structures of novel molecules derived from extremophilic or extreme-tolerant microorganisms. These microbial products will be classified according to which of the six extremophile classifications they fall under. The optimum (opt.) or tolerated (tol.) growth conditions of the source microorganism are included when this information is available. For classification purposes, if a microorganism falls under multiple classifications, it is grouped under the dominant environmental factor.

Enzymes from extremophiles (sometimes called extremozymes) have been a hot topic in the literature since their discovery due to their significant potential for biotechnological applications. As a result of this interest there are a number of current reviews^9–11 on their isolation and uses, and hence they will not be discussed in this review.

2 High temperature

Thermophiles were the first branch of extremophiles to be found, and are arguably the most widely investigated extremophiles at the current time. Accordingly, significantly more novel molecules have been isolated from thermophilic microorganisms than from any of the other classifications of extremophiles. Thermophilic fungi have been found, and are seen to produce novel molecules as reported below; however, these microorganisms have much lower optimum growth temperatures than those observed for thermophilic bacteria or archaea.¹²

2.1 Secondary metabolites

A range of secondary metabolites have been isolated from diverse thermophilic sources. The isolation of thermorubin, from a mildly thermophilic actinomycete (opt. 48–53 °C) collected from a soil sample in Pavia, Italy, was reported in 1964. The substance showed strong activity against Gram-positive bacteria, less activity against Gram-negative bacteria and little to no activity against yeasts and fungi.¹³ The structure was originally reported¹⁴ in 1972 to contain xanthone and anthracene moieties; however, later physical and chemical studies showed thermorubin to be oxanaphthacene 1.¹⁵

The thermophilic fungus Streptomyces thermoviolaceus ssp. pigens var. WR-14 has been found to be a source not only of the previously isolated molecule granaticin 2, but also of the novel granaticin precursor dihydrogranaticin 3, and two related molecules 4 and 5.¹⁶ Granaticin 2 and the novel derivative granaticinic acid 6 were later isolated from another thermophilic Streptomyces sp. XT-11989.¹⁷

Sibyllimycine (5,6,7,8-tetrahydro-3-methyl-8-oxo-4-azaindolizidine, 7) was isolated from a thermophilic Actinomyces (strain CB21) from a 60 °C hot spring at Lake Tanganyika in Cape Banza, Africa.¹⁸

Siderophore S_VK21 (2,3-dihydroxybenzoylglycyl-threonine, 8) was isolated from the thermoresistant (tol. 60 °C) bacterium Bacillus licheniformis. S_VK218 is a fragment of the known siderophore bacillibactin 9, which is produced by B. subtilis. S_VK218 and bacillibactin 9 may be synthesized by the same enzyme in both bacteria, with the thermoresistant bacteria having disrupted activity in the specific condensing domain responsible for forming the cyclic trilactone.¹⁹

Thermozymocidin was isolated from strain IPV F-4333 of the mildly thermophilic fungus Mycelia sterilia (opt. 40–45 °C) in 1972. Thermozymocidin showed no activity against Gram-positive or Gram-negative bacteria but was highly active against a range of filamentous fungi and yeasts.²⁰ The structure of thermozymocidin was reported separately in 1972 as 10.²¹ Thermozymocidin 10 was also separately isolated from the thermophilic fungus Myriococcum albomyces and renamed myriocin. Synthetic studies confirmed the stereochemistry of the three stereogenic centres.²²

The mildly thermophilic soil actinomycete Thermoactinomyces strain TM-64 (opt. 45 °C) has been found to produce a thiazole-containing alkaloid, TM-64.²³ Structural elucidation²⁴ followed by total synthesis²⁵ confirmed the structure of TM-64 11.

Strain IMBAS-11A of Microbispora aerate, a moderate thermophile (opt. 50 °C), was isolated from penguin excrement from Livingston Island, in the Antarctic. A novel alkaloid (microbiaeratin 12) and the known compound bacillamide (referred to as microbiaeratinin) were isolated from this species. Structural elucidation showed microbiaeratin 12 to be the acetate of TM-64 11.²⁶

A novel carotenoid glycoside ester was isolated from the red-pigmented moderately thermophilic (opt. 60 °C)²⁷ bacterium Meiothermus ruber in 1999. The structure of this carotenoid was determined to be 13 with the 6′′-position of the β-glucose acetylated by a series of 12 C₁₀–C₁₇ fatty acids, two of which were branched.²⁸

A trisulfide with antitumor activity, BS-1, was isolated from the thermophile (opt. 68–70 °C)²⁹Bacillus stearothermophilus UK563 in 1991.³⁰ Structural elucidation showed BS-1 to be bis(2-hydroxyethyl)trisulfide 14,³¹ a compound whose synthesis was reported in a 1942 patent³² but had never been isolated from nature.³¹ Further investigations indicated that BS-1 activates macrophages to the cytolytic stage.³³

Cyclic polysulfides have been isolated from hyperthermophilic archaea of the sulfur-metabolising genus Thermococcus. Thermococcus tadjuricus (strain Ob9) from a marine hydrothermal system near Obock (Djibouti) and Thermococcus acidaminovorans (strain Vc6bk) from an Italian volcano were seen to produce a wide range of novel cyclic polysulfides (Table 2, 15–37) with four different polysulfide cores, as well as the known cyclic polysulfide lenthionine (1,2,3,5,6-pentathiepane, 38)^34,35

Table 2 Cyclic polysulfides from Thermococcus species

Compound	Core	R^1	R^2	n
Lenthionine 38	C	H	H	—
15	A	CH3	CH3	—
16	A	C2H5	CH3	—
17	A	i-C4H9	H	—
18	A	i-C4H9	CH3	—
19	A	C2H5	i-C4H9	—
20	A	i-C4H9	i-C3H7	—
21	A	i-C4H9	i-C4H9	—
22	A	Benzyl	CH3	—
23	A	Benzyl	i-C4H9	—
24	A	IndMe	i-C4H9	—
25	B	i-C4H9	CH3	—
26	B	i-C4H9	i-C4H9	—
27	B	IndMe	i-C4H9	—
28	C	i-C4H9	H	—
29	C	i-C4H9	CH3	—
30	C	i-C4H9	i-C3H7	—
31	C	i-C4H9	i-C4H9	—
32	C	Benzyl	i-C4H9	—
33	C	IndMe	i-C4H9	—
34	D	i-C4H9	—	1
35	D	CH3	—	2
36	D	i-C4H9	—	2
37	D	i-C4H9	—	3

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2.2 Polyamines

Spermine 39, putrescine 40 and spermidine 41 are naturally occurring polyamines of which two or more are present in high concentrations in all growing cells, and are considered essential for cell proliferation.^36,37 Investigation into the polyamine profiles of thermophilic microorganisms has led to the discovery of numerous novel polyamines (see Table 3), which are thought to play a role in the stabilization of nucleic acids at the extreme temperatures they inhabit.³⁸ A recent review has been published on the polyamines of Thermus thermophilus.³⁹

Table 3 Novel polyamines from various thermophiles

Polyamine	Isolation microorganism	Microorganism source	Year	Ref.
Thermine 42	Thermus thermophilus (opt. 65–72 °C)	Hot spring at Mine, Japan	1975	40,41
Thermospermine 43			1979	40,42
Caldopentamine 44			1982	40,43
Homocaldopentamine 45			1983	40,44
N ^4-Bis(aminopropyl)norspermidine(a.k.a. tetrakis-3-aminopropyl)ammonium 46			1987	40,45
Thermopentamine 47			1990	40,46
N ^1-Aminopropylagmatine 48	T. thermophilus disruption mutant		2005	47
N ^4-(Aminopropyl)norspermidine 49	Thermoleophilum album and T. minutum (opt. 60 °C)	Hot springs at Arkansas, USA and Yellowstone National Park, Wyoming, USA	1990	48–50
N ^4-(Aminopropyl)spermidine 50
N ^4-Bis(aminopropyl)spermidine 51			1992	51
Caldoheptamine 52	Thermotoga maritima (opt. 80 °C)	Geothermally heated sea floors in Italy and the Azores	1986	52,53
Thermohexamine 53	Bacillus schlegelii (opt. 70 °C)	Surface sediment from a Swiss lake	1992	51,54
Homothermohexamine 54

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2.3 Nucleosides

Thermophiles have been found to contain novel nucleosides which are thought to play a role in stabilizing DNA against heat stresses by decreasing conformational flexibility.⁵⁵ The isolation of four novel ribose-methylated nucleosides (55, 56, 57 and 58) was reported in 1987 from the thermohalophilic (opt. 87 °C and pH 3.5–5)^56,57 archaeon Sulfolobus solfataricus (previously Caldariella acidophilia⁴¹) and the thermophiles Thermoproteus neutrophilus (opt. 88 °C)⁵⁸ and Pyrodictium occultum (opt. 105 °C) collected from a submarine solfataric field in the bay of Porto Levante, Vulcano island, Italy.⁵⁹T. neutrophilus contained all four nucleosides, S. solfataricus contained all but ac⁴Cm 57 and P. occultum contained all but m²₂Gm 58.⁶⁰ That same year a novel derivative of the Y nucleoside, mimG 59, was also isolated from S. solfataricus.⁵⁶ This highly fluorescent nucleoside was also found in two other thermophilic archaea, Thermoproteus neutrophilus (opt. 88 °C)⁵⁸ and Pyrodictium occultum.^59,61

5′-Deoxyguanosine 60 was found to be produced by Thermoactinomycete sp. A6019 from a soil sample from Northwood, Rhode Island, USA. This molecule had previously been synthesized,⁶² but had not been isolated from a natural source.⁶³

Novel nucleosides N27.4 61 and N31.4 62 were isolated from two thermophilic bacteria, Thermodesulfobacterium commune and Thermotoga maritima, and six thermophilic archaea, Pyrobaculum islandicum, Pyrodictium occultum, Thermococcus sp., Thermodiscus maritimus, Thermoproteus neutrophilus and Pyrococcus furiosus as well as two mesophilic archaea in 1992.⁶⁴

2.4 Osmolytes

An osmolyte is a small, highly soluble molecule which is either accumulated or synthesized by a cell. Osmolytes (also known as compatible solutes) play an important role in maintaining cell volume and fluid balance, without interfering with the central metabolism of the cell. With the increased stresses of extreme environments, it is not surprising that a number of novel osmolytes have been isolated from extremophiles. Novel osmolytes from extremophiles (also known as extremolytes) have aroused considerable interest due to their potential biotechnological uses in the protection of biological macromolecules and cells from damage by environmental changes.^65,66

In 1983 methanophosphagen (2,3-cyclopyrophosphoglycerate 63) was isolated^67,68 from the thermophilic (opt. 65–70 °C) methanogen Methanobacterium thermoautotrophicus, which was collected from sewage sludge.⁶⁹

Di-mannosyl-di-myo-inositol-phosphate (di-2-O-β-mannosyl-di-myo-inositol-1,1′-phosphate 64) and the 1,3′-isomer of di-myo-inositol-phosphate (di-myo-inositol-1,3′-phosphate 65) were isolated from two thermophilic (opt. 80 °C) Thermotoga bacteria, Thermotoga maritima and Thermotoga neapolitana, which were collected from a shallow submarine hot spring near Lucrino, Italy.^52,70,71

Archaeoglobus fulgidus, a thermophilic (opt. 83 °C) archaeon collected from hot sediments from a hydrothermal system near Vulcano island, Italy, was found to produce the osmolyte di-glycerol-phosphate 66.^72–74

2.5 Carbohydrates

A series of novel polysaccharides have been isolated from thermophilic microorganisms. Streptococcus thermophilus is a thermophilic (grows at 45 °C but not at 15 °C) bacteria isolated from yoghurt, cheese and their starter cultures.⁷⁵ The species status of S. thermophilus has been widely debated. S. thermophilus was reclassified as Streptococcus salicarius ssp. thermophilus in 1984⁷⁶ before being reinstated as a species in 1991,⁷⁵ which has been supported in the recent literature.⁷⁷

In 1990 an exopolysaccharide with the repeating unit 67 was reported from S. thermophilus strains CNCMI 733, 734 and 735.⁷⁸ The structures of a further two exopolysaccharide repeating units, 68 from S. thermophilus strain SFi39 and 69 from S. thermophilus strain SFi12, were reported in 1997.⁷⁹ Later the same year, the exopolysaccharide produced by S. thermophilus strain OR 90 was reported, with the repeating unit consisting of branched heptasaccharide 70.⁸⁰ The repeating unit of the exopolysaccharide of S. thermophilus strain SE 71 was reported in 2001. This exopolysaccharide contains 0.4 equivalents of O-acetyl groups per repeating unit.⁸¹ Finally, a further exopolysaccharide, 72, from S. thermophilus strain EU20, was also reported in 2001.⁸²

Thermus thermophilus ⁶⁰ (strain HB8) was found in 2005 to produce a novel polysaccharide 73, which consisted of a disaccharide repeating unit to which a trisaccharide chain is linked nonstoichiometrically.^40,83

The structures of the components of the two teichoic acid fractions from the Gram-positive thermophilic (opt. 55–65 °C) bacteria Geobacillis thermoleovorans (previously Bacillus thermoleovorans)⁸⁴ strain Fango, collected from a range of hot soil and mud samples, were reported in 2006.^85,86 The major teichoic acid fraction TA1 was seen to consist of two different repeating units 74 and 75; however, it could not be determined in what ratio. The minor teichoic acid fraction TA2 showed a lot more variability. Although the major repeating units were the same as for TA1 (74 and 75), it also had the repeating units 76, 77, 78 and 79 (in order of decreasing abundance). The study was unable to determine whether these structures are present as a single, highly variable glycerol polymer with non-stoichiometric appendages or whether there are different chains which behave the same chromatographically.⁸⁵

2.6 Lipids

2.6.1 Core lipids and fatty acids. The lipids of thermophilic archaea are characterized by three key structural differences to the lipids isolated from other microorganisms. They contain isoprenoid (phytanyl) chains with 15, 20, 25 or 40 carbons, rather than the straight chains of other organisms. Two of these chains are linked via ether linkages to glycerol or a polyol, rather than the ester linkage found elsewhere. The glycerol found in archaea, 2,3-di-O-sn-glycerol 80, has the reverse stereochemistry to that found in other organisms.^87,88 Novel lipids have also been isolated from thermophilic microorganisms which contain the more traditional ester linkage.

In 1974, Langworthy et al. reported the isolation of glycolipid B, a novel polyol of undetermined structure from the thermoacidophilic Solfolobus acidocaldarius strain 98.3.⁸⁹ At a similar time, de Rosa et al. reported the isolation of “calditol”, a novel nonitol from the thermophile Solfolobus solfataricus (previously Caldariella acidophilia). Calditol was assigned a branched chain nonitol structure 81 with no stereochemistry determined.⁹⁰ In 1995 the calditol of S. acidocaldarius was assigned the structure 82 by Sugai et al.⁹¹ Total synthesis in 1999 confirmed the structure of the calditol from S. acidocaldarius to be 83⁹² which was identical to the calditol of S. solfataricus, as determined by further studies.⁹³

A novel class of lipids (Table 4) was first isolated from thermoacidophiles in the 1970s. These molecules feature two C₄₀ isoprenoid chains which are linked to either two molecules of glycerol (the glycerol-dialkyl-glycerol-tetraethers – GDGTs) or to a molecule of glycerol and a molecule of calditol (glycerol-dialkyl-calditol-tetraethers – GDNTs (as calditol was originally thought to be a nonitol (see above)). The alkyl chains were originally assigned an antiparallel orientation (84),⁹⁹ but more recent studies have indicated that the diglycerol tetraethers may actually be present as a combination of regioisomers (84 + 85).¹⁰⁰ The chirality of the C₄₀ chains has been confirmed by total synthesis¹⁰¹ and the chains contain 0–4 cyclopentane groups (a–e), with the amount of cyclisation observed to increase as growth temperature rises.¹⁰² The two alkyl chains may be the same or different (see Table 4, 86–106). An isomer (101) containing a “broken” C₄₀ chain (f) has also been isolated.⁹⁷

Table 4 Tetraether lipids of archaea

GDGT / GDNT (isoprenyl chains)	Year isolated	Microorganism
GDGT (a + a) 86, GDGT (b + b) 87, GDGT (c + c) 88	1977	Solfolobus solfataricus (previously Caldariella acidophila) strain MT3^94,95 and Thermoplasma acidophilum (GDGT (a + a))^96
GDGT (d + d) 89, GDGT (e + e) 90, GDNT (a + a) 91, GDNT (b + b) 92, GDNT (c + c) 93, GDNT (d + d) 94, GDNT (e + e) 95	1980	Solfolobus solfataricus strain MT4^90,95
GDGT (a + f) 96, GDGT (a + b) 97, GDGT (b + c) 98, GDGT (c + d) 99, GDGT (d + e) 100, GDNT (a + f) 101, GDNT (a + b) 102,GDNT (b + c) 103, GDNT (c + d) 104, GDNT (d + e) 105	1983	Sulfolobus solfataricus ^97
GDGT (a + c) 106	1988	Thermoproteus tenax strain Kra-1^98

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A novel core lipid, FU, was isolated from the total lipid fraction of Methanothermus fervidus in 1998.¹⁰³Methanothermus fervidus is a hyperthermophilic (opt. 83 °C) methanogen isolated from an Icelandic hot spring.¹⁰⁴ The most likely structure for FU is a bridged version of GDGT (a + a) 107, although the exact position of the bridge has not been fully confirmed.¹⁰³

The novel fatty acid 15,16-dimethyl-30-glyceryloxytriacontanoic acid 108 was isolated from a thermophilic (opt. 80 °C) and mildly halotolerant (tol. 0.25–3.75% NaCl) strain of anaerobic bacteria isolated from geothermally heated sea floors in the Azores and Italy.^52,105

Acid hydrolysis of the glycolipids of the thermophiles Thermus scotoductus X-1 (opt. 65 °C)¹⁰⁶ and Thermus filiformis Tok4 A2 (opt. 73 °C)¹⁰⁷ showed the presence of novel long-chain 1,2-diols, 109 (major component) and 110 (minor component), as well as trace amounts of 111 and 112. These diols were found to be linked to glycan head groups, which were not fully characterized.¹⁰⁸T. scotoductus X-1 was collected from hot tap water in Iceland and T. filiformis Tok4 A2 was collected from a hot spring in New Zealand.¹⁰⁷

2.6.2 Glyco- and phospholipids.  

2.6.2.1 Ether-linked

The polar lipids of archaea are typically substituted on the free hydroxyl group of the glycerol head group and have been reviewed in the literature.^87,109,110 Only the isolation of novel structures not included in these reviews will be discussed herein.

The structure of a major glycolipid from Thermus oshimai NTU-063 (opt. 70 °C)¹¹¹ isolated from Wu-rai hot springs, Taiwan, was reported in 2004 to be β-Glcp-(1→6)-β-Glcp-(1→6)-β-Glcp-NAcyl-(1→2)-α-Glcp-(1→1)-glycerol diester. The N-acyl group is either C_15:0 or C_17:0 and the O-acyl esters of the glycerol are mainly from C_15:0–C_18:0 including straight, isobranched and anteisobranched fatty acids.¹¹² Previously it had been shown that GL-1 of T. oshimai SPS-11 (from Portuguese hot springs) has the same carbohydrate sequence and similar fatty acid composition,^111,113 but this study did not determine the linkage or configuration, hence it cannot be claimed that they have identical carbohydrate moieties.¹¹²

Also in 2004 the major polar glycolipids of Meiothermus taiwanensis ATCC BAA-400 were reported as having the structure β-Galp-(1→6)-β-Galp-(1→6)-β-Gal-NAcyl-(1→2)-α-Gly-(1→1)-glycerol diester where the glycerol esters were mainly iso- and anteiso-branched C_15:0 and C_17:0 and the N-acyl is a C_17:0 or hydroxyl C_17:0 fatty acid.¹¹⁴ Glycolipids from a further four Meiothermus species, M. ruber, M. cerbereus, M. silvanus (originally Thermus silvanus)¹¹⁵ and M. chliarophilus (originally Thermus chliarophilus)¹¹⁵ (opt. 60 °C,²⁷ 55 °C,¹¹⁶ 55 °C¹¹⁷ and 50 °C¹¹⁷ respectively) were reported in 1999. Each strain produced glycolipids with one of three carbohydrate backbones (A–C), of which the stereochemistry of the linkages was not determined, and showed two bands of glycolipids by thin layer chromatography (GL-1a and GL-1b) due to differing substitution on the polar head group (see Table 5).¹¹⁸M. cerbereus was first isolated from a hot spring in the Geysir geothermal region of Iceland.¹¹⁶

Table 5 Glycolipids from Meiothermus species

Strain	Backbone	GL-1a		GL-1b
		R^1 (%)	R^2 (%)	R^1 (%)	R^2 (%)
M. ruber	A	2-OH C17:0 (>90)	C15:0 (89), C16:0 (3), C17:0 (8)	C15:0 (30), 3-OH C15:0 (13), C17:0 (27), 3-OH C17:0 (30)	C15:0 (91), C16:0 (3), C17:0 (8)
M. cerbereus	B	2-OH C17:0 >90)	C15:0 (2), C16:0 (10), C17:0 (18)	3-OH C17:0 (>90)	C15:0 (76), C16:0 (10), C17:0 (14)
M. silvanus	B	2-OH C17:0 (83), 2-OH C16:0 (12)	C15:0 (75), C16:0 (5), C17:0 (20)	C15:0 (43), C16:0 (10), C17:0 (42), 3-OH C17:0 (5)	C15:0 (77), C16:0 (6), C17:0 (17)
M. chliarophilus	C	2-OH C17:0 (>90)	C15:0 (74), C16:0 (5), C17:0 (20)	C17:0 (>90)	C15:0 (72), C16:0 (4), C17:0 (23)

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The isolation of two novel polar lipids AGI 113 and AI 114 from Aeropyrum pernix K1 which contained glucosylinositol as the polar head group was reported in 1999.¹¹⁹Aeropyrum pernix is a hyperthermophilic (opt. 90–95 °C) archaeon which was isolated from a coastal solfataric thermal vent off Kodakara-Jima Island, Japan.¹²⁰ A structurally similar novel glycolipid 115 was isolated from the thermohalophilic (grows at up to 93 °C and lyses in the presence of less than 3.5% NaCl) archaeon Thermococcus celer, which was collected from a marine water hole on Vulcano island, Italy.^121,122

In 1999, the structures of five novel neutral glycolipids (116–120, Table 6) were reported.¹²³ These glycolipids had been isolated from Thermoplasma acidophilum, a thermoacidophile (opt. 59 °C and pH 1.0–2.0) collected from a smoldering coal pile in the USA, and consisted of GDGTs which were substituted on one or both of the free hydroxyls.⁸

Table 6 Neutral glycolipids from Thermoplasma acidophilum

Compound		R^1	R^2	Isoprenyl chains^a
a Most abundant isoprenyl chain listed; see Table 4 for structures.
116	GL-1a	β-Gulose	OH	b + b
117	GL-1b	α-Glucose	OH	a + a
118	GL-2a	β-Gulose	β-Gulose	b + b
119	GL-2b	β-Gulose	α-Glucose	b + b
120	GL-2c	α-Glucose	α-Glucose	b + b

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2.6.2.2 Ester-linked. A novel glycolipid was isolated from the thermophile (opt. 65–72 °C) Thermus thermophilus (previously Flavobacterium thermophilum¹²⁴) HB-8 in 1974. Its structure was determined to be Galf-(1→2)-Galp-(1→6)-GlcN(15-methylhexadecanoyl)-(1→2)-Glcp-diglyceride.¹²⁵ The structure of two major glycolipids GL1 121 and GL2 122 and a phospholipid PGL 123 from T. thermophilus strain Samu-SA1 was published in 2006 (shown with most abundant chain lengths).¹²⁶ The thermohalophilic strain Samu-SA1 (opt. 75 °C and 2% w/v NaCl) was isolated from a depth of 60 m in a hot spring on Mount Grillo, Naples, Italy.¹²⁷

The novel phosphoglycolipids PGL1 124 and PGL2 125 were isolated from the thermophiles Thermus oshimai NTU-063, Thermus thermophilus NTU-077, Meiothermus ruber NTU-124 (originally Thermus ruber¹¹⁵) and Meiothermus taiwanensis NTU-220 (opt. 70 °C,¹¹¹ 65–72 °C,⁴⁰ 60 °C²⁷ and 55 °C¹²⁸ respectively), which were collected from hot springs in Taiwan. While PGL1 124 is structurally similar to a phosphoglycolipid from the radiation-tolerant Deinococcus radiodurans,¹²⁹ PGL2 125 is the first phospholipid identified with a 2-acylalkyldio-1-O-phosphate moiety. The fatty acids were found to be mainly iso-branched C_15:0, C_16:0 and C_17:0 and anteiso-branched C_15:0 and C_17:0 fatty acids with the ratio of iso to anteiso fatty acids increasing at higher culture temperatures. In all strains but T. oshimai, the ratio of PGL2 to PGL1 increased with increasing culture temperature.¹³⁰

Two novel glycolipids 126 and 127 with the very rare α(1→4) diglucosyl structure were isolated from the thermophile Thermotoga maritima in 1992.¹³¹

Roseiflexus castenholzii is a reddish-brown thermophilic (opt. 50 °C) bacteria which was isolated from a bacterial mat in a Japanese hot spring.¹³² The lipid composition of R. castenholzii strain HLO8^T has been investigated and the dominant compounds in the total lipid extract were found to be alkane-1,2-diol-based glycosides with the major isomers being 128 and 129. Wax esters were present as minor components ranging from 37 to 40 carbons in length.¹³³

A novel Lipid A with the unique structure 130 was isolated from the Gram-negative thermophile Aquifex pyrophilus in 2000.^134,135

Pentacyclic tetra-ol 131 and two glucosamine derivatives 132 and 133 were isolated from the glycolipid fraction of Bacillus acidocaldarius in 1976. In the same study the diglucosyl glycerides of B. acidocaldarius were partially characterized to be 134 and its derivatives, which included glucosyl-N-acylglucosaminylmonoacyl glycerol and trace amounts of glucosyl-N-acylglucosaminyl glycerol.^136,137B. acidocaldarius is a thermoacidophile (opt. 60–65 °C, pH 3–4) isolated from a range of thermal acid environments.¹³⁸ In 1976, the structure of a bacteriohopanetetrol that had been isolated in 1973 from the bacteria Acetobacter xylinum¹³⁹ was revised by Rohmer and Ourssion to also be 131.¹⁴⁰

2.6.3 Lipoquinones. Isoprenoid quinones (lipoquinones) are components of bacterial membranes, which consist of a quinone moiety with an isoprenyl side chain. The nature of the quinone and the length and degree of saturation of the isoprenyl chain present differs between the different species of bacteria. A review on the distribution of isoprenoid quinones in bacteria and archaea was published in 1981.¹⁴¹

Several novel quinone moieties have been identified during investigations into the lipoquinones of thermophiles. Caldariellaquinone (CQ) 135, the first sulfur-containing bacterial lipoquinone, was first isolated from the thermoacidophile Sulfolobus solfataricus (previously Caldariella acidophilia⁵⁶) in 1975,¹⁴² and the structure reported as CQ-6H₁₂ in 1977.¹⁴³ In 1986, a further novel quinone moiety, tricyclic quinone (SSQ) 136, was isolated from the same bacterium as SSQ-5H₁₀.^144,145

Thermoplasmaquinone (TPQ) was first isolated from Thermoplasma acidophilum in 1983.¹⁴⁶ The structure was reported two years later as 2,[5 or 8]-dimethyl-3-heptaprenyl-1,4-naphthoquinone (TPQ-7).¹⁴⁷ It was not until 2001 that the position of the second methyl group was confirmed to be at C8 (137).¹⁴⁸Thermoplasma acidophilum is a thermoacidophile (opt. 59 °C and pH 2), which was originally isolated from a burning coal refuse pile in Friar Tuck mine in Indiana, USA.⁸

Sulfolobusquinone (SQ) 138 was originally isolated from Acidianus ambivalens (previously known as Sulfolobus ambivalens¹⁴⁹ and Desulfurolobus ambivalens¹⁵⁰) in 1986 as SQ-6H₁₂.¹⁵¹Acidianus ambivalens is a thermoacidophilic (opt. 80 °C and pH 2.5) archaeon isolated from a solfataric waterhole in the Leirhnukur fissure, Iceland.^150,152

A menaquinone containing a novel fully saturated cyclic isoprenoid chain, Δ14-cyclopentyl MK-6H₁₀139, was isolated from the archaeon Pyrobaculum organotrophum in 1991.¹⁵³ This archaeon is extremely thermophilic (optimum growth at 100 °C) and was isolated from solfataric waters in Iceland and the Azores.¹⁵⁴

3 Low temperature

The term “psychrophile” was first used in 1902, referring to a bacterium capable of growing at 0 °C.¹ A large number of the natural products isolated from psychrophiles or psychrotolerant microorganisms have been isolated from cold water sources, and these have recently been reviewed by Lebar et al.¹⁵⁵ Representatives of all of the major taxa are capable of inhabiting temperatures below 0 °C, making the psychrophiles one of the more diverse branches of the extremophiles.⁵ To date, the only novel molecules isolated from psychrophiles are secondary metabolites.

3.1 Secondary metabolites

The novel secondary metabolites of psychrophiles have largely been found to be based on modified peptides, with some exceptions. Psychrotolerant bacteria have been found to be a source of novel diketopiperazines. Diketopiperazine 140 was co-isolated with five known diketopiperazines and two phenazine alkaloid antibiotics from the bacterium Pseudomonas aeruginosa, and its structure determined to be cyclo(L-proline-L-methionine). This psychrotolerant bacterium was found associated with a bioactive Antarctic sponge, Isodictya setifera, which was collected from a depth of 30–40 m from Hut Point and Danger Slopes on Ross Island, Antarctica.¹⁵⁶

Another novel diketopiperazine 141 and two novel linear peptides 142 and 143 were isolated from the cell-free culture supernatant of the psychrohalophilic (growth at 4 °C and opt. 1.5–3.5% NaCl)¹⁵⁷ bacterium Pseudoalteromonas haloplanktis TAC125, which was isolated from Antarctic seawater near the Dumont d'Urville Antarctic Station in 1992. This organism also produced two diketopiperazines 144 and 145 which were previously only known synthetically, and five previously isolated diketopiperazines. Linear peptides 142 and 143 were found to be stable to bacterial proteolytic enzymes.¹⁵⁸

Three cyclic peptides, mixirins A–C (146–148), were collected from a psychrotolerant Bacillus sp. strain MIX-62, isolated from sea mud near the Arctic pole. These compounds inhibited the growth of human colon tumor cells.¹⁵⁹

Penicillium ribium (strain IBT 16531) is a psychrotolerant fungi which was collected from the soil under a redcurrant bush (Ribes species) growing in tundra in Wyoming, USA.¹⁶⁰ Two novel metabolites, psychrophilin A 149 and cycloaspeptide D 150, as well as the known compound cycloaspeptide A, were isolated from this strain in 2004. Psychrophilin A 149 was the first natural cyclic peptide isolated that possesses a nitro group rather than an amino group.¹⁶¹

Further molecules belonging to this series, psychrophilin B 151 and C 152, were isolated later that year from another novel psychrotolerant fungi Penicillium rivulum strain IBT24420. In 2004, it was reported that this same fungi also produces the alkaloids communesins G 153 and H 154.¹⁶²

Penicillium algidum, also found in soil under a Ribes species, this time in Greenland, was found to produce cycloaspeptides A and D 150, as well as the novel compound psychrophilin D 155, which exhibits moderate activity in the P388 murine leukaemia cell line.¹⁶³

Usimines A–C (156–158) and the known compound usinic acid were isolated from the Antarctic lichen Stereocaulon alpinum,¹⁶⁴ which was collected from Barton peninsula on King George Island, Antarctica, in 2003. These compounds exhibited moderate inhibitory activity against protein tyrosine phosphatase 1B (PTP1B).¹⁶⁵ The isolation of stereocalpin A 159 from the same lichen has also been reported. This cyclic depsipeptide exhibited marginal cytotoxicity against three human solid tumor cell lines and weakly inhibited PTP1B.¹⁶⁶

In 2004, two novel molecules, helquinoline 160 and N-acetylkynuramine 161, were isolated from psychrotolerant Janibacter limosus culture Hel-1 which was collected from the North Sea. Helquinoline 160 exhibited moderate activity against Bacillus subtilis, Streptomyces viridochromogenes Tü 57 and Staphylococcus aureus.

Three novel pyrrolosesquiterpenes, glyciapyrroles A–C (162–164), and three known diketopiperazines were isolated from a psychrotolerant actinomycete, Streptomyces sp. strain NPS008187, which was isolated from a marine sediment sample collected from Alaska.¹⁶⁷

4 High pressure

Piezophiles (barophiles) are typically isolated from the bottom of the ocean, where bacterial inhabitants must be both piezophilic and at least psychrotolerant to survive (unless isolated from a heat vent). The effects of warming up these bacteria when they are isolated could potentially explain why early developments in piezophile research were quite slow.¹⁶⁸

4.1 Secondary metabolites

Piezophiles (barophiles) are one of the more widely investigated branches of extremophiles in relation to the isolation of novel secondary metabolites. The majority of the secondary metabolites isolated are cyclic. Five novel compounds, (+)-formylanserinone B 165, (−)-epoxyserinone A 166, (+)-epoxyserinone B 167, hydroxymethylanserinone B 168 and deoxyanserinone B 169, were isolated from a mixed culture of two Penicillium corylophium strains collected at 1335 m, along with two known compounds, anserinone A and (+)-anserinone B. Hydroxymethylanserinone B 168 and deoxyserinone B 169 were not fully purified. (+)-Formylanserinone B 165 selectively inhibited murine leukaemia cells over murine solid tumor cells, and inhibited the MDA-MB-435 cell line in the sulforhodamine B assay.

(−)-Epoxyserinone A 166 and (+)-epoxyserinone B 167 showed less potent inhibition in this assay, with (+)-epoxyserinone B 167 exhibiting inhibition of murine cancer cell lines.¹⁶⁹

Guaymasol 170 and epiguaymasol 171 were isolated from a Bacillus species culture CNA-995, which was collected from a deep-sea (1834 m) sediment core collected from the Guaymas Basin. The known compound guaymasone was also isolated.¹⁷⁰

An actinomycete Streptomyces species PC1/B2 was isolated from a deep-sea sediment sample collected at a depth of 4680 m in the Pacific ocean, north-north-east of Majuro, Marshall Islands, in 1982. γ-Indomycinone 172 was reported from a culture broth of this bacterium 13 years later, along with two other known members of the pluramycin class of antibiotics.¹⁷¹

Streptokordin 173 and four known compounds were isolated from an actinomycete (KORDI-3238) of the Streptomyces genus found in a deep sea sediment sample from the Ayu trough. Streptokordin 173 showed cytotoxic activity against several human cancer cell lines, yet exhibited no activity against a variety of bacteria or fungi.¹⁷²

Phenazine 174 was isolated in 2007 from a bacterium of the Bacillus sp., which was isolated from a Pacific deep sea sediment sample at a depth of 5059 m, along with six known compounds. Compound 174 has shown cytotoxicity towards P388 cells using the sulforhodamine-B assay in preliminary screens.¹⁷³

Aspergillus fumigatus strain BM939, a fungus isolated from the sea bottom (760 m) at the mouth of the Oi river, Sizuoka prefecture, Japan, has been found to produce a number of novel secondary metabolites. In 1995, the isolation of tryprostatin A 175 and B 176 was reported.¹⁷⁴ Isolation of a further related compound, demethyoxyfumitremorgin C 177, as well as four other known compounds, was reported in 1996.^175,176 These compounds exhibited inhibitory activity against cell-cycle progression of mouse tsFT210 cells in the M phase,¹⁷⁵ as did acetophthalidin 178, also isolated from Aspergillus fumigatus strain BM939 in 1996.¹⁷⁷ Also in 1996, spirotryprostatin A 179 and B 180 were isolated from the same fungus, and were found to inhibit cell cycle progression of tsFT210 cells at the G2/M phase.¹⁷⁸ Finally in 1997, the isolation of cyclotryprostatins A–D (181–184) was reported. As with the spirotryprostatins, these molecules inhibited tsFT210 cells in the G2/M phase.¹⁷⁹

The novel violet pigment 185 has been isolated from Shewanella violacea strain DSS12,¹⁸⁰ a barohalophsychrophile (opt. 30 MPa, 3% NaCl and 8 °C) Gram-negative bacterium which was isolated from Ryukyu trench at a depth of 5110 m.¹⁸¹

Caprolactins A 186 and B 187 were isolated from an unidentified Gram-positive bacteria, designated PC12/1000-B4, that was collected from a deep-sea (5065 m) sediment sample north-north-west of Majuro in the Pacific Ocean. These molecules exhibited cytotoxic activity towards human epidermoid carcinoma (KB) cells and human colorectal adenocarcinoma (LoVo) cells, as well as displaying antiviral activity towards Herpes simplex type II virus.¹⁸²

In 1987, bisucaberin 188 was isolated from the Gram-negative bacteria Alteromonas haloplanktis strain SB-1123 which was collected from deep-sea mud at a depth of 3300 m, off the coast of the Aomori Prefecture.¹⁸³ Bisucaberin 188, a siderophore, was found to sensitize tumor cells to cell lysis by non-activated macrophages.^183,184

Macrolactins A–F (189–194), macrolactinic acid 195 and isomacrolactinic acid 196 were isolated from C-237, a unidentified Gram-positive, halophilic bacterium collected from the north Pacific at a depth of 980 m in 1989. Different cultures of this bacteria produced different macrolactins, with no one culture producing all of them. Macrolactin A 189 showed inhibitory activity against Bacillus subtilis and Staphylococcus aureus, as well as significant antiviral activity and cytotoxicity towards cancer cells.¹⁸⁵ The stereochemistry of macrolactins B 190 and F 194 was reported in 1992,¹⁸⁶ and the assumption that this stereochemistry would be common to all the macrolactins was confirmed when the total synthesis of macrolactins A 189, E 193 and macrolactinic acid 195 was reported in 1998.¹⁸⁷

A series of diketopiperazines 197–201 were isolated from an actinomycete bacteria Streptomyces fungicidicus, which was collected from Pacific sediment at approximately 5000 m depth. These molecules exhibited anti-barnacle larval attachment activity, indicating potential as anti-foulants.¹⁸⁸

The cyclic tetrapeptide MKN-349A 202 was isolated from an actinomycete of the genus Nocardiopsis, strain MO349, collected from Pacific sediment from the Clarion–Clipperton fracture zone at a depth of 3000 m. The structure of cyclic tetrapeptide 202 was determined to be cyclo(L-isoleucyl-L-prolyl-L-leucyl-L-prolyl). Although the crude extract exhibited cytotoxicity towards leukaemia cell line K-562, this activity did not result from 202.¹⁸⁹

The larger cyclic peptide halobacillin 203, which exhibited moderate human cancer cell cytotoxicity, was isolated from Bacillus species culture CND-914, collected from a marine sediment core taken at a depth of 124 m near the Guaymas Basin in Mexico.¹⁹⁰

Antiadhesin 204 was isolated from Bacillus licheniformis (strain 603) a mildly thermophilic and halotolerant (opt. 43–48 °C, tol. 15% NaCl) bacterium. This Gram-positive bacterium was isolated from a mixture of drilling fluid and subsurface thermal (56 °C) water at a depth of 2100 m. Antiadhesin 204 exhibits strong anti-adhesive activity against bacteria, as well as relatively high growth-suppressing activity against Corynebacterium variabilis.¹⁹¹

4.2 Carbohydrates

To date, five exopolysaccharides isolated from piezophiles have had their structures reported. The bacterium Alteromonas macleodii ssp. fijiensis was isolated from a deep-sea hydrothermal field on a rift system of the North Fiji basin at a depth of 2000 m. A. macleodii is halophilic, with optimum growth between 25–40 g L⁻¹ of NaCl, and produced an exopolysaccharide with the repeating unit 205.^192,193 A further two exopolysaccharides from A. macleodii ssp. fijiensis have been partially characterized. One exopolysaccaride (an undesaccharide with three side chains) was isolated from A. macleodii ssp. fijiensis biovar. deepsane in 2002. This bacterium was collected from a hydrothermal vent polychaete annelid Alvinella pompejana, at a depth of 2625 m from a rift system of the East Pacific Rise.¹⁹⁴ The second uncharacterised exopolysaccharide was produced by A. macleodii ssp. fijiensis biovar. medioatlantica. which was collected from the hydrothermal vent shrimp Rimicaris exoculata at a depth of 3500 m on the mid-Atlantic Ridge.¹⁹⁵

Bacterial strain 1644, which was determined to be of the Alteromonas species, was isolated from tissues from an invertebrate Alvinella caudate collected at a depth of 2600 m on the East Pacific Rise.¹⁹⁶ The structure of the repeating unit 206 of the exopolysaccharide produced by this organism has been partially determined.^197–199 This exopolysaccharide was found to contain a novel glucuronic acid derivative, 3-O-[(R)-1-carboxyethyl]-D-glucuronic acid (3-O-Lac-β-D-GlcpA).¹⁹⁶

Two novel exopolysaccharides from Pseudoalteromonas species have been reported. Compound 207 was isolated from moderately halophilic Pseudoalteromonas sp. SM9913 (opt. 3% NaCl) which was found in a deep-sea sediment sample collected near the Okinawa trough at a depth of 1855 m.²⁰⁰Pseudoalteromas strain HYD721, collected from Alvinella pompejana, produced an exopolysaccharide with a branched octasaccharide repeating unit 208.^201,202 The polychaete annelid Alvinella pompejana was found near an active hydrothermal vent on the East Pacific Rise at a depth of 2600 m.

The Gram-negative bacterium Vibrio diabolicus strain CNCM I-1629 was also collected from a depth of 2600 m in a rift system of the East Pacific Rise in 1991.²⁰³ This bacterium was found to produce an exopolysaccharide with the repeating unit 209.²⁰⁴

5 High salt

Organisms which thrive in high salt environments (halophiles) primarily have to be able to survive osmotic stress. Halophilic and halotolerant microorganisms survive this stress by the accumulation of osmolytes or by maintaining cytoplasmic salt concentration (KCl) close to that of the surrounding medium.²⁰⁵ Halophiles are another branch of extremophiles that contain representatives of all three domains of life.¹

5.1 Secondary metabolites

Relatively few novel secondary metabolites have to date been isolated from halophiles. Bacillus endophyticus strain SP31 was isolated from a hypersaline microbial mat on San Salvador Island, Bahamas. It was found to produce the known algaecide bacillamide A and two novel analogues, bacillamide B 210 and bacillamide C 211.²⁰⁶

Vibrio parahaemolyticus is a halophilic (opt. 3% NaCl) Gram-negative bacteria originally isolated as the causative agent in seafood poisoning in 1950.²⁰⁷ Several indole-based natural products have been isolated from strains of this bacterium isolated from different sources. Vibrindole A 212 and another known indole derivative were isolated from strain B2 of V. parahaemolyticus collected from the toxic mucus secreted by the boxfish Ostracion cubicus. Vibrindole A showed inhibitory activity against Staphylococcus aureus, Staphylococcus albus and Bacillus subtilis.²⁰⁸ Although known previously from synthesis,²⁰⁹ this was the first isolation of this molecule from a natural source. In 2003, the novel indole derivative 213 and two other molecules, 214 and 215, previously only known synthetically,^210,211 along with several known compounds, were isolated from V. parahaemolyticus strain Bio249, which was obtained from the North Sea.²¹²

Two novel citrinin dimers, pennicitrinone C 216 and penicitrinol B 217, were isolated together with 11 known citrinin dimers, from a halotolerant fungal strain B-57 which was characterized as Penicillium citrinum, collected from the Jilantai salt field in Inner Mongolia. Pennicitrinone C 216 exhibited anti-oxidant activity against 1,1-diphenyl-2-picrylhydrazyl radicals.²¹³

The novel mycosporine-like amino acid euhalothece-362 218 was isolated from a halophilic cyanobacterium designated LK-1 of the Euhalothece cluster, from a hypersaline pond in Eilat, Israel.^214,215

5.2 Polyamines

Three novel polyamines, N³-aminopropylcadaverine 219, aminopentylnorspermidine 220 and N,N′-bis(3-aminopropyl)cadaverine 221, were isolated in 1988 from Halococcus acetoinfaciens, a halotolerant (tol. 6% NaCl) Gram-negative bacterium.²¹⁶

5.3 Nucleosides

The modified nucleoside 1-methylpseudouridine 222, which had not been previously found in nucleic acids, was isolated from the tRNA of Halococcus morrhuae and appears to be unique to archaea.²¹⁷Halococcus morrhuae is a halophile (opt. 3.5–4.5 M NaCl) isolated from saline lakes, salterns and salted products.²¹⁸

5.4 Osmolytes

A comprehensive review of the compatible solutes (osmolytes) in halotolerant and halophilic microorganisms was published in 2005.²¹⁹ This review shows that halophilic or halotolerant bacteria and eukaryotes tend to accumulate neutral osmolytes, whereas halophilic or halotolerant archaea tend to accumulate negatively charged solutes.²¹⁹ The structures of eight novel osmolytes first isolated in halophiles and halothermophiles are highlighted here.

2-Sulfotrehalose 223 was first isolated from archaea of the Natronococcus and Natronobacterium species.²²⁰ These archaea are usually isolated from hypersaline soda lakes and are haloalkaliphilic (opt. 20–22% NaCl and pH 9.5, and 20–25% and pH 8.5–9.5 respectively).²²¹

It has been reported that 37% of the total soluble compounds of Methanococcus thermolithotrophicus consist of the novel osmolyte β-glutamate (β-aminoglutaric acid 224). Methanococcus thermolithotrophicus is an anaerobic thermohalophile (opt. 65 °C and 4% NaCl) which was collected from geothermally-heated sea sediments off the coast of Naples, Italy.^222,223 β-Glutamate 224 had previously been found as a major component of anoxic sea sediments^224,225 but prior to this isolation in 1989, a plausible bacterial source had not been identified.²²⁶

The novel osmolyte N^ε-acetyl-β-lysine 225 was isolated from the methanogens Methanosarcina thermophilia TM-1 and Methanogenium cariaci JR1 in 1990.²²⁷Methanosarcina thermophilia is a thermohalophile (opt. 50 °C and 0.005–1.2 M NaCl) and was isolated from a 55 °C sludge digester.^228,229 The mesophilic Methanogenium cariaci grows in the presence of 0.17–1.4 M NaCl, and was isolated from the Cariaco trench.²³⁰

In 1992, di-myo-inositol-1,1′-phosphate 226 was isolated from the thermohalophilic (opt. 100–103 °C and 30 g L⁻¹ NaCl) archaeon Pyrococcus woesei which was collected from marine solfataras at Vulcano island, Italy.^231,232 β-Galactopyranosyl-5-hydroxylysine (GalHL 227) was also isolated from Italian archaea. When grown on peptone-containing medium, the thermohalophilic (opt. 85 °C and 1.8–6.5% NaCl) archaeon Thermococcus litoralis DSM 5474, collected from shallow submarine solfataras at Lucrino, Naples and Porto di Levante, Vulcano island, was found to produce GalHL 227.^233,234

In 2006, the novel compatible solute 1-glyceryl-1-myo-inosityl phosphate 228 was found in Aquifex pyrophilus, a microaerophilic thermohalophile (opt. 85 °C and 3% NaCl) isolated from a submarine hydrothermal vent system north of Iceland. The stereochemical configuration of the compound has yet to be established.^134,235

Petrotoga miotherma is a strictly anaerobic thermohalophilic (opt. 55 °C and 2% NaCl) bacterium which was found in 2007 to produce a novel solute MGG (α-D-mannopyranosyl-(1→2)-α-D-glucopyranosyl-(1→2)-glycerate 229).^236,237

In 2007, the novel solute DAGAP (di-N-acetyl-glucosamine phosphate 230) was isolated from Rubrobacter xylanophilus. This thermophilic (opt. 60 °C) and halotolerant (tol. 6% NaCl) Gram-positive bacterium was isolated from an industrial run-off near Salisbury, UK, and has been found to be extremely radiation-resistant.^238,239

5.5 Carbohydrates

The carbohydrate backbone of the lipopolysaccharides of Vibrio parahaemolyticus²⁰⁷ 012 strain OP204 was reported in 1991²⁴⁰ and that of Vibrio parahaemolyticus 02 strain V95–269 was reported in 2003 (231 and 232 respectively).²⁴¹ The structure of the 5,7-diamino-3,5,7,9-tetradeoxy-non-2-ulosonic acid (Non1A) isolated from the lipopolysaccharide of strain V95–269 was determined to be 233.²⁴² Earlier (in 1976), a bag-shaped cell wall peptidoglycan was isolated from Vibrio parahaemolyticus strain A55 when the whole cell was treated with sodium dodecylsulfate.²⁴³ This peptidoglycan was determined to have the repeating unit 234, with roughly 30% of the A₂pm residues being cross-linked, either between two of the tetrapeptide substituents on the same glycan as shown in 234 or between tetrapeptides on neighbouring glycans.²⁴⁴

A novel exopolysaccharide with the repeating unit 235 was found to be produced by the extremely halophilic (opt. 17% NaCl) archaeon Haloferax mediterranei strain R4 (originally Halobacterium mediterranei), which was isolated from a salt pond near Alicante, Spain.^245–249

5.6 Lipids

5.6.1 Core lipids and fatty acids. In 1986, it was reported that the thermoalkaliphilic (opt. 70–75 °C, pH 8.2–8.5) Gram-negative bacterium Thermomicrobium roseum differed from other thermophiles in that it lacked glycerol-derived membrane lipids. Instead it had a novel series of straight-chain and methyl-branched 1,2-diols 236–246 as head groups. Thermomicrobium roseum was isolated from Toadstool Spring in the Lower Geyser Basin of Yellowstone National Park, USA.^250–252

A halophilic bacterium of the Bacillus species isolated from the Burgas salt pans in Bulgaria was shown to comprise a complex fatty acid composition consisting of 41 identifiable fatty acids ranging in length from C₁₀ to C₂₄. These fatty acids included four novel 4-methylated fatty acids, 4,9-dimethyldecanoic acid 247, 4,11-dimethyldodecanoic acid 248, 4,13-dimethyltetradecanoic acid 249 and 4,10-dimethyldodecanoic acid 250, and two novel 2-methylated fatty acids, 2,13-dimethyltetradecanoic acid 251 and 2,12-dimethyltetradecanoic acid 252.²⁵³

5.6.2 Glyco- and phospholipids (ether-linked). The glyco- and phopholipids of halophilic archaea have the same basic structure as those of the thermophilic archaea, with two C₂₀ isoprenoid chains attached to a glycerol and the remaining hydroxyl being linked to a phosphonate or glycoside (or combination of the two).

The major phospholipid of Halobacterium salinarum (formerly Halobacterium cutirubrum) has, after revision, been determined to be monomethylated 2,3-diphytanyl-sn-glycerol-1-phospho-3′-sn-glycerol-1′-phosphate 253.²⁵⁴ Previously it was thought that the structure was non-methylated.^255–257 A novel glycolipid, lipid X 254, and a novel phospholipid, lipid Y 255, have been isolated from the purple membrane of a genetically engineered strain (L33) of Halobacterium salinarum.²⁵⁸ Lipid X 254 (also known as GlyC) is a phospholipid dimer consisting of sulfo-triglucosyl-diether-1 (S-TGD-1) esterified to the phosphonate group of phosphatidic acid (PA), and is induced by osmotic shock.²⁵⁹

In 1994, 256 was isolated as the major glycolipid of a halophilic (opt. 4 M NaCl) archaeon, strain 172, which was isolated from sea sand in Japan.^260,261 A structurally similar novel glycocardiolipid S-GL-2 257 was isolated from the archaeon Haloferax volcanii strain ATTC 29605 in 2003.²⁶²Haloferax volcanii (originally known as Halobacterium volcanii)²⁴⁷ is a halophilic (opt. 1.7–2.5 M NaCl) archaeon which was first isolated from sediment from the bottom of the Dead Sea.²⁶³

Halorubrum sp. MdS1 is a halophilic archaeon isolated from the salterns of Margherita si Savoia, Italy, and in 2004 it was found to produce a novel cardiolipin analogue which consists of a sulfodiglycosyl-diphytanylglycerol ester derivative of the phosphate group of phosphatidic acid (S-DGD-5-PA, 258).²⁶⁴

5.6.3 Lipoquinones. Two previously unknown quinone moieties were isolated as minor components from Natronobacterium gregoryi strain SP2, an alkaliphilic, extremely halophilic (optimum growth at pH 9.5 and 20–22% NaCl) archaeon isolated from an East African Soda Lake.^221,265 The quinones were methylated menaquinones, with MMK-8 and MMK-8(H₂) having an additional methyl group at C-5 or C-8 (259), and DMMK-8 and DMMK-8(H₂) having two additional adjacent methyl groups on C-5/C-6 or C-7/C-8 (260).²⁶⁵

6 High pH

To date very few novel structures from alkaliphilic or alkali-tolerant microorganisms have been reported. Enzymes from alkaliphiles, however, have made a large impact due to their industrial applications as biological detergents and in the production of cyclodextrin.²⁶⁶

6.1 Secondary metabolites

Two secondary metabolites have been isolated from an alkaliphilic Streptomyces species from County Durham, UK. Lactonamycin Z 261 (shown with relative stereochemistry for the sugar molecule), a molecule exhibiting antibiotic and antitumor activity, was isolated from an alkaliphilic strain (opt. pH 9) of the Gram-positive, halotolerant (tol. 7% w/v NaCl) actinomycete Streptomyces sanglieri.²⁶⁷ This alkaliphilic strain AK 623 was isolated from soil from a pine wood in Hamsterley Forest, County Durham, UK.²⁶⁸

The isolation of pyrocoll 262 from the alkaliphilic (opt. pH 9) Streptomyces species AK 409 was reported in 2003. Streptomyces species AK 409 was isolated from a steel waste tip soil sample from Consett, County Durham, UK.²⁶⁹ Pyrocoll 262, which has previously been synthesized²⁷⁰ and is a known component of cigarette smoke,²⁷¹ had not previously been isolated from a natural source.²⁶⁹

6.2 Carbohydrates

The repeating unit of the O-specific chain structure for the major 263 and minor 264 components of the lipopolysaccharide fraction of Halomonas magadensis strain 21 MI were reported in 2003.^272,273Halomonas magadiensis (formerly Halomonas magadii) is an alkaliphilic (opt. pH 9.5), halotolerant (tol. 20% salts) Gram-negative bacterium isolated from Lake Magadi, a soda lake in the East African Rift Valley.²⁷⁴

Halomonas pantelleriense is a Gram-negative moderately haloalkaliphilic (opt. 10% NaCl and pH 9.0) bacterium isolated from hard sand from a volcanic lake on Pantelleria island, Italy.²⁷⁵ The structure of the repeating unit of an O-chain polysaccharide from this bacterium was determined to be 265 in 2006.²⁷⁶ An α-glucan with an unprecedented O-allyl-substituted hexose was reported in 2007.²⁷⁷ Two core oligosaccharides, OS1 266 and OS2 267, from the same bacterium were reported in 2008, with the structures differing in one heptose residue. It was also established that the previously determined O-chain repeating unit 265 was linked via the QuiNAc residue to the core.²⁷⁸

6.3 Lipids

In 2004, the isolation of an unusual Lipid A was reported from Halomonas magadiensis strain 21 M1.²⁷⁴ This lipid A is characterized by a peculiar acylation pattern (268–275, Table 7) with the main species being penta-acetylated lipid A (270) and tetra-acetylated lipid A 274, which both lack a primary 12:0(3-OH) residue at the reducing GlcN.²⁷⁹

Table 7 Lipid A compounds of Halomonsa magadiensis

Compound	268a	268b	269a	269b	270	271a	271b	272a	272b	273	274	275a	275b
a Fatty acid absent from this position.
R	C10:0	C10:0	H	H	C10:0	H	H	C10:0	C10:0	H	H	H	H
R′	C16:0	C18:1	C16:0	C18:1	H	C16:0	C18:1	^a	^a	H	^a	^a	^a
R″	PO3^−	PO3^−	PO3^−	PO3^−	PO3^−	PO3^−	PO3^−	PO3^−	H	PO3^−	PO3^−	PO3^−	H

---

7 Low pH

Microorganisms capable of surviving low pH have been isolated from a range of sources around the world, both man-made, e.g. Berkeley Pit Mine, and natural, e.g. acidic hot springs. These microorganisms have been found to produce diverse secondary metabolites, which have a range of biological activities.

7.1 Secondary metabolites

A number of structurally interesting secondary metabolites with compelling biological activity have been isolated from microorganisms which live in low pH environments. Pseudomonas cocovenenans, an acid-tolerant (tol. pH 4) archaeon, is a source of three biologically active secondary metabolites.²⁸⁰ Toxoflavin 276 and bongkrekic acid 277 were first reported in 1934. Toxoflavin 276, an intensely yellow compound, was found to exhibit rather high antibiotic activity against a range of bacteria.^281,282 Bongkrekic acid 277 was found to be the causative factor for frequent fatal food poisonings in Java after consumption of P. cocovenenans-contaminated “bongkrek” (a local coconut product).²⁸³ It was not until 1973, however, that the structure of bongkrekic acid 277 was fully elucidated.²⁸⁴ Finally, the isolation of a β-lactam antibiotic, MM 42842 278, from the same archaeon was reported in 1987.²⁸⁰ MM 42842 278 was found to be structurally similar to sulfazecin 279, with the only difference being an additional methyl group on the β-lactam ring.²⁸⁵

Sulfazecin 279 was isolated from Pseudomonas acidophilia (strain G-6302) in 1981.²⁸⁶ Its enantiomer, isosulfazecin 280, was isolated from the moderate acidophile (opt. pH 4.5–7.0) Pseudomonas mesoacidophilia (strain SB-7231).^287–289 Bulgecins A–C (281–283) were isolated as monosodium salts from the same bacterium. These molecules did not exhibit antibacterial activity independently but showed strong synergism with the β-lactam antibiotics, resulting in bulge formation in Gram-negative bacteria and increased cell lysis. Bulgecin A 281, which was the major component, exhibited the strongest activity.^290–292

The pentacyclic triterpene hopene-b 284 was isolated from a novel acidothermophilic (opt. at pH 2.6–2.8 and 58–60 °C) bacterium isolated from the volcanic area of Naples, Italy, along with the previously isolated compound, hopene-1.²⁹³

Seven zeaxanthin glycosides were isolated from a mutant of the acidothermophilic (opt. pH 3 and 81 °C) archaeon Sulfolobus shibatae, which was originally found in an acidic hot spring.^294,295 The three all-(E) zeaxanthin glycosides had been previously isolated but the remaining four zeaxanthin glycosides, 285–288, are the first naturally occurring (Z)-isomers of zeaxanthin glycosides.²⁹⁵

The Berkeley Pit Lake is an acidic (pH 2.5), metal-laden lake formed when infiltrating ground water filled the abandoned Berkeley Pit Copper mine in Butte, Montana, USA. Over 40 different bacteria, protists, fungi, algae and protozoans have been identified from this source, from which to date over 20 novel natural products have been isolated.

Three novel cytotoxic tyrosine derivatives (289–291) and three guaiane sesquiterpenes (292–294), were isolated from a Pithomyces Ellis = Sporodesmia species in 2003. Compound 290 was seen to act as a 5-HT_(2a) receptor ligand, indicating potential as an anti-migraine or anti-hypertensive agent,²⁹⁶ while 289 and 291 and its methyl ester showed only marginal activity.

Caspase-1 and matrix metalloproteinase-3 (MMP-3) inhibition assays were used to isolate three sesquiterpenes (295–297) and coumarin derivative 298 from the filamentous Penicillium fungus Pitna 4 in 2004.²⁹⁷

Assay-guided isolation was also used to collect a novel spiroketal berkelic acid 299 from the same fungus, as well as a known γ-pyrone, spiciferone A. As well as inhibitory activity against caspase-1 and MMP-3, berkelic acid exhibited selective activity against ovarian cancer cell line OVCAR-3 (GI₅₀ of 91 nM) in a 60 human cell line National Cancer Institute (NCI) antitumor screen.²⁹⁸

Caspase-1 and MMP-3 inhibition was also used to isolate two hybrid polyketide-terpenoid metabolites, berkeleydione 300 and berkeleytrione 301, in 2004 from a Penicillium rubrum fungus isolated from a depth of 885 ft. Berkeleydione 300 has demonstrated selective activity against non-small-cell lung cancer NCI-H460 in the same NCI antitumor screen.²⁹⁹

Three years later, the isolation of berkeleyacetals A–C (302–304) was reported from the same fungus. All three berkeleyacetals inhibited caspase-1 and MMP-3, with berkeleyacetal C 304 being the most active and also exhibiting inhibitory activity towards non-small-cell lung cancer NCI H460 in the NCI antitumor screen.³⁰⁰

Most recently, berkeleyamides A–D (305–308) were isolated from the same fungus, again identified on the basis of their activity against caspase-1 and MMP-3.³⁰¹

7.2 Carbohydrates

An exopolysaccharide produced by Lactobacills acidophilus strain LMG9433 was determined to have the repeating unit 309.³⁰²Lactobacillus acidophilus has been found to be acid-tolerant (tol. pH 3).³⁰³

7.3 Lipids

Two fatty acids with a terminal cycloheptane ring, 310 and 311, were isolated from a novel mildly thermoacidophilic (opt. 48 °C and pH 3.5) Bacillus species. This was the first reported isolation of ω-cycloheptane fatty acids.³⁰⁴ In a later publication, a novel α-hydroxy-C₁₈ fatty acid with an ω-terminal cycloheptane ring (ω-cycloheptyl-α-hydroxyundecanoate 312) was isolated from the same bacterium.³⁰⁵

Ferroplasma acidiphilum strain Y^T is an acidophilic (opt. pH 1.7) archaeon isolated from a bioleaching pilot plant in Bakyrtchick, Kazakhstan, from which the major constituent of the total lipids (approximately 55%) was determined to be 313, a novel glycophospholipid with the GDGT (b + b) lipid core.^306,307

8 Conclusions

As demonstrated by this review, extremophiles are a rich source of novel secondary metabolites. However, when compared to the large number of extremophilic microorganisms which have been reported, very few have been screened for the production of interesting secondary metabolites.

Investigations into the biology and ecology of extremophiles are much more common, which is encouraged by the similarities of some extremophiles to the early life on earth and also the potential they represent for extraterrestrial life.³⁰⁸ This situation may also be attributed to the inherent difficulties involved in cultivating extremophilic microorganisms, some of which cannot survive under normal laboratory conditions and therefore cannot be cultured using traditional techniques. Only 4% of the bacteria which have been successfully cultured are extremophiles.³⁰⁹

While advances in laboratory techniques have led to cultivation of some previously inaccessible extremophiles, this can be very labour-intensive. The collection of metagenomes from extreme environments offers the potential to circumvent the need to cultivate extremophilic microorganisms entirely.³¹⁰ Although to date this technique has been largely used for identification of extremozymes,³⁰⁹ the resultant DNA libraries could be transferred into host organisms which can then be tested for the production of secondary metabolites. This heterologous expression approach to secondary metabolite isolation provides a tremendous opportunity to readily access further examples of unusual natural products from organisms that are difficult to culture, such as extremophiles.³¹⁰

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