Editorial: Are natural products the solution to antimicrobial resistance?

Infections caused by bacterial pathogens are a major cause of morbidity and mortality worldwide. Although the successful treatment of such infections by antibiotic drugs is widely regarded as a major medical breakthrough of the 20^th century, this achievement may not be sustainable in the future, as bacteria have counteracted antibiotic pressure and developed or acquired resistances that render formerly efficacious drugs inactive. With the threat of a potential return to a pre-antibiotic era on the horizon, the scientific community, regulatory agencies, health care authorities and politicians have recently intensified their efforts to counteract the upcoming crisis. Because the natural product research community was the critical enabler of the 20^th century breakthrough, we found it timely to assemble a special issue of NPR on the current and future role of natural products in alleviating the rising issue of antimicrobial resistance.

“The most fruitful basis of the discovery of a new drug is to start with an old drug” is a famous statement by Nobel prize winner James Black. It is definitely true for antibiotics, as exemplified by the race between bacterial resistance development and refined versions of β-lactam antibiotics, which has been conducted over at least five generations of drugs. In this issue, efforts to find improved versions of colistin are highlighted in the review ‘Recent advances and perspectives in the design and development of polymyxins’ by Rabanal and Cajal (DOI: 10.1039/x0xx00000x). Colistin’s clinical use has been limited due to its severe nephrotoxic side effects, but due to an alarming spread of resistance in Enterobacteriaceae to β-lactams, reliance on this ‘last resort’ antibiotic is increasing. Consequently, natural product chemistry is not directed towards the classical goals of increasing potency or breaking resistance, but towards limiting kidney accumulation and minimizing nephrotoxic side effects. Another innovative approach to better utilize existing drugs is to hybridize them with a second functional moiety. This can be either another antibiotic in order to achieve dual targeting, or a transporting moiety to enhance uptake of the antibiotic. For both variants, clinical proof-of-concept studies are currently ongoing, as outlined by Klahn and Brönstrup in their review ‘Bifunctional antimicrobial conjugates and hybrid antimicrobials’ (DOI: 10.1039/c7np00006e).

While the further exploitation of existing antibiotic scaffolds may help to alleviate the antibiotic crisis in the short term, a sustainable pipeline of antibiotic drugs requires that novel, innovative chemical matter is discovered and optimized for human use. Historically, microbial natural products have been the major source of such novel antibiotics. However, the pharmaceutical industry has mostly abandoned natural product discovery efforts, and formerly fruitful sources like actinomycetes have already been exploited to a large extent. Whether natural product research (still) has the potential to overcome the antibiotic discovery void is therefore a major topic of this special issue. A positive answer that is substantiated by an overview of past, present and future research themes is provided in the highlight by Wright entitled ‘Opportunities for natural products in 21st century antibiotic discovery’ (DOI: 10.1039/c7np00019g). A focused viewpoint on peptides that have been converted into compact, rigidified small molecule frameworks and their antimicrobial activities is given by Walsh in his article ‘Are highly morphed peptide frameworks lurking silently in microbial genomes valuable as next generation antibiotic scaffolds?’ (DOI: 10.1039/c7np00011a). Furthermore, the review by Challis and colleagues on ‘Antibiotics from Gram-negative bacteria: a comprehensive overview and selected biosynthetic highlights’ (DOI: 10.1039/c7np00010c) impressively illustrates that the study of unusual, less-explored microorganisms is rewarded by discoveries of known as well as unusual biosynthetic machineries that indeed produce novel and bioactive chemical matter. The concept reviewed by Bugni and colleagues goes one step further. Instead of studying a microorganism in isolation, exposure to other organisms in its environment triggers the biosynthesis of bioactive metabolites as mediators of symbiotic interactions. The interactions of microbes with animals, plants, fungi, or other bacteria and the associated natural products are reviewed in the article ‘Symbiosis-inspired approaches to antibiotic discovery’ (DOI: 10.1039/c7np00009j).

In addition to the in-depth analysis of natural antibiotic ‘chemical matter’, this special issue also highlights the biological space spanned by clinically validated and promising novel targets. Remarkably, most marketed antibiotics address hotspots in complex biosynthetic machineries, whose impairment has drastic consequences for the bacterial cell that are hard to repair or compensate for. Among these, peptidoglycan biosynthesis is a cellular process that can be perturbed by antibiotics with clinically proven success. Within the complex process of peptidoglycan synthesis, lipid II, one of the structurally most conserved, non-proteinaceous molecules in bacterial cells, has been spotted as an “Achilles’ heel” for antibiotic attack. Intriguingly, nature has ‘invented’ at least 5 classes of structurally divergent lipid II binders, as discussed by Schneider and colleagues in their review ‘Targeting a cell wall biosynthesis hot spot’ (DOI: 10.1039/c7np00012j).

Another clinically validated cellular target structure is protein translation, the molecular understanding of which has been vastly improved through advances in structural biology. Most natural product researchers could name a variety of ‘famous’ antibiotics interfering with protein translation – macrolides, tetracyclines, pleuromultilins, etc. – but until recently antimicrobial peptides (AMPs) would hardly have made it onto this list. While the most studied target of AMPs is the bacterial membrane, subclasses of AMPs can pass through the membrane by non-lytic mechanisms and exert antibiotic effects through intracellular targets. A prime example of this is proline-rich AMPs that bind to the ribosomal exit tunnel, as presented by Wilson and colleagues in their highlight article ‘Proline-rich antimicrobial peptides targeting protein synthesis’ (DOI: 10.1039/c7np00020k). Targeting the reverse process, the degradation of peptides and proteins by Clp protease, is an attractive strategy for future antibiotics, as this highly conserved machinery plays (amongst other functions) a role in bacterial persistence. Malik and Brötz-Oesterhelt summarize the current state of knowledge about various classes of natural products and their different mechanisms of deregulating Clp proteolysis in their review ‘Conformational control of the bacterial Clp protease by natural product antibiotics’ (DOI: 10.1039/c6np00125d).

In summary, this special issue provides scientific evidence that natural product research is in a privileged position to address and solve the present bacterial resistance issue and the closely linked antibiotic discovery void. Microorganisms continue to be a rich source of novel chemical matter, and of antibiotic leads. In addition, natural products serve as pointers to novel or unexplored cellular targets and mechanisms (e.g. ADEP’s → Clp protease or griselimycin → DnaN). We are convinced that after studying the contributions in this issue, the reader will be inspired about multiple ways of tackling the antimicrobial resistance problem.

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