Addressing Antibiotic Resistance: New Strategies for Targeting the Bacterial Cell Wall
Van Leeuwenhoek Lecture on BioScience.
Nathaniel Martin obtained his PhD in 2004 from the Department of Chemistry at the University of Alberta (Canada) on research into naturally occurring antimicrobial peptides. Upon completion of his PhD he moved to the University of California Berkeley where he worked as a postdoctoral fellow in the lab of Michael Marletta. In Berkeley Nathaniel studied the enzyme nitric oxide synthase (NOS) with the specific aim of developing new inhibitors and mechanistic probes to better understand the process by which NOS converts L-arginine into nitric oxide. In 2007 Nathaniel began his independent research career at Utrecht University where he built a dynamic research group working in the fields of medicinal chemistry and chemical. Fundamental to the work carried out in Nathaniel's research group is the application of synthetic organic chemistry to address biologically interesting and medicinally relevant questions. Specifically, the group's research focuses on using new (bio)chemical approaches to combat infectious disease as well as developing new molecular tools with which to study epigenetic processes.
Nathaniel has received a number of grants and awards in support of his research including the NWO VENI (2007) and VIDI (2010) grants as well as the ERC consolidator grant (2016). He was also recently named as one of the top three young medical chemists in Europe (in voting for the EFMC Prize Young Medicinal Chemists in Academia). In 2018 Nathaniel will move his research group to the Institute of Biology (IBL) at Leiden University where he will be appointed as full professor in Natural Products Chemistry.
To overcome resistance mechanisms it is essential that new antibiotics operate by novel modes of action. Current research in the Martin group is concerned with developing compounds that interfere with bacterial cell wall synthesis via mechanisms that differ from clinically used antibiotics.
In one of our research lines we recently described the preparation of semi-synthetic lipopeptide antibiotics derived from the naturally occurring antimicrobial peptide nisin. In doing so, the lipid II-binding N-terminus nisin was modified to provide antibacterially active and proteolytically stable lipopeptide derivatives. These semi-synthetic constructs display potent inhibition of bacterial growth, with activities approaching that of nisin itself. Good activity is observed against clinically relevant bacterial strains including MRSA and VRE. Experiments with membrane models indicate that these constructs operate via a lipid II-mediated mode of action without causing pore formation.
A second line of research in the group is concerned with the calcium dependent antibiotics (CDAs). We recently reported the total synthesis of the CDA laspartomycin C and established that its antibacterial mechanism is due to tight binding of the bacterial phospholipid undecaprenyl phosphate (C55-P). While the CDAs have come to clinical prominence over the past decade, virtually no structural data exist in support of the bacterial targets ascribed to these compounds. We here report the 1.28 A resolutiom crystal structure of laspartomycin C bound to a soluble C55-P analogue, geranyl-phosphate. The structure reveals the key role played by calcium in facilitating the interactions between the antibiotic and its phospholipid target. Notably, this structure is the first of a CDA bound to its bacterial target and may provide a blueprint towards the development of novel antibacterial therapies.
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