Issue 10, 2022

Mechanistic insights into the C55-P targeting lipopeptide antibiotics revealed by structure–activity studies and high-resolution crystal structures

Abstract

The continued rise of antibiotic resistance is a global concern that threatens to undermine many aspects of modern medical practice. Key to addressing this threat is the discovery and development of new antibiotics that operate by unexploited modes of action. The so-called calcium-dependent lipopeptide antibiotics (CDAs) are an important emerging class of natural products that provides a source of new antibiotic agents rich in structural and mechanistic diversity. Notable in this regard is the subset of CDAs comprising the laspartomycins and amphomycins/friulimicins that specifically target the bacterial cell wall precursor undecaprenyl phosphate (C55-P). In this study we describe the design and synthesis of new C55-P-targeting CDAs with structural features drawn from both the laspartomycin and amphomycin/friulimicin classes. Assessment of these lipopeptides revealed previously unknown and surprisingly subtle structural features that are required for antibacterial activity. High-resolution crystal structures further indicate that the amphomycin/friulimicin-like lipopeptides adopt a unique crystal packing that governs their interaction with C55-P and provides an explanation for their antibacterial effect. In addition, live-cell microscopy studies provide further insights into the biological activity of the C55-P targeting CDAs highlighting their unique mechanism of action relative to the clinically used CDA daptomycin.

Graphical abstract: Mechanistic insights into the C55-P targeting lipopeptide antibiotics revealed by structure–activity studies and high-resolution crystal structures

Supplementary files

Article information

Article type
Edge Article
Submitted
24 Dec 2021
Accepted
18 Jan 2022
First published
21 Feb 2022
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2022,13, 2985-2991

Mechanistic insights into the C55-P targeting lipopeptide antibiotics revealed by structure–activity studies and high-resolution crystal structures

T. M. Wood, M. R. Zeronian, N. Buijs, K. Bertheussen, H. K. Abedian, A. V. Johnson, N. M. Pearce, M. Lutz, J. Kemmink, T. Seirsma, L. W. Hamoen, B. J. C. Janssen and N. I. Martin, Chem. Sci., 2022, 13, 2985 DOI: 10.1039/D1SC07190D

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