Issue 4, 2021

Assessment of the rules related to gaining activity against Gram-negative bacteria

Abstract

In the search for new antibacterial compounds, we repositioned an antimalarial compound class by derivatising it based on the so-called “eNTRy” rules for enhanced accumulation into Gram-negative bacteria. We designed, synthesised and evaluated a small library of amino acid modified compounds together with the respective Boc-protected analogues, leading to no substantial improvement in antibacterial activity against Escherichia coli wild-type K12, whereas more distinct activity differences were observed in E. coli mutant strains ΔtolC, D22, ΔacrB and BL21(DE3)omp8. A comparison of the activity results of the E. coli mutants with respect to the known rules related to enhanced activity against Gram-negative bacteria revealed that applicability of the rules is not always ensured. Out of the four amino acids used in this study, glycine derivatives showed highest antibacterial activity, although still suffering from efflux issues.

Graphical abstract: Assessment of the rules related to gaining activity against Gram-negative bacteria

Supplementary files

Article information

Article type
Research Article
Submitted
04 dek 2020
Accepted
30 yan 2021
First published
03 mar 2021

RSC Med. Chem., 2021,12, 593-601

Assessment of the rules related to gaining activity against Gram-negative bacteria

H. Ropponen, E. Diamanti, A. Siemens, B. Illarionov, J. Haupenthal, M. Fischer, M. Rottmann, M. Witschel and A. K. H. Hirsch, RSC Med. Chem., 2021, 12, 593 DOI: 10.1039/D0MD00409J

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