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

DOI: 10.1039/D1SC07190D DOI Help

Authors: Thomas M. Wood (Leiden University; Utrecht University) , Matthieu R. Zeronian (Utrecht University) , Ned Buijs (Leiden University) , Kristine Bertheussen (Leiden University) , Hanieh K. Abedian (Leiden University) , Aidan V. Johnson (Leiden University) , Nicholas M. Pearce (Utrecht University) , Martin Lutz (Utrecht University) , Johan Kemmink (University of Groningen) , Tjalling Seirsma (University of Amsterdam) , Leendert W. Hamoen (University of Amsterdam) , Bert J. C. Janssen (Utrecht University) , Nathaniel I. Martin (Leiden University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Chemical Science , VOL 98

State: Published (Approved)
Published: February 2022
Diamond Proposal Number(s): 19800

Open Access Open Access

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.

Diamond Keywords: Bacteria

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography

Added On: 01/03/2022 09:23

Discipline Tags:

Pathogens Antibiotic Resistance Infectious Diseases Health & Wellbeing Biochemistry Chemistry Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)