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

Wood TM, Zeronian MR, Buijs N, Bertheussen K, Abedian HK, Johnson AV, Pearce NM, Lutz M, Kemmink J, Seirsma T, Hamoen LW, Janssen BJC, Martin NI

Chem Sci 13 (10) 2985-2991 [2022-03-09; online 2022-02-21]

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.

DDLS Fellow

Nicholas Pearce

PubMed 35382464

DOI 10.1039/d1sc07190d

Crossref 10.1039/d1sc07190d

pmc: PMC8905900
pii: d1sc07190d

Publications 9.5.0