Sophisticated natural products as antibiotics

Kim Lewis (), Richard E. Lee (), Heike Brötz-Oesterhelt, Sebastian Hiller, Marina V. Rodnina, Tanja Schneider, Markus Weingarth and Ingo Wohlgemuth
Additional contact information
Kim Lewis: Northeastern University
Richard E. Lee: St Jude Children’s Research Hospital
Heike Brötz-Oesterhelt: Interfaculty Institute of Microbiology and Infection Medicine
Sebastian Hiller: University of Basel
Marina V. Rodnina: Max Planck Institute for Multidisciplinary Sciences
Tanja Schneider: University of Bonn, University Hospital Bonn
Markus Weingarth: Utrecht University
Ingo Wohlgemuth: Max Planck Institute for Multidisciplinary Sciences

Nature, 2024, vol. 632, issue 8023, 39-49

Abstract: Abstract In this Review, we explore natural product antibiotics that do more than simply inhibit an active site of an essential enzyme. We review these compounds to provide inspiration for the design of much-needed new antibacterial agents, and examine the complex mechanisms that have evolved to effectively target bacteria, including covalent binders, inhibitors of resistance, compounds that utilize self-promoted entry, those that evade resistance, prodrugs, target corrupters, inhibitors of ‘undruggable’ targets, compounds that form supramolecular complexes, and selective membrane-acting agents. These are exemplified by β-lactams that bind covalently to inhibit transpeptidases and β-lactamases, siderophore chimeras that hijack import mechanisms to smuggle antibiotics into the cell, compounds that are activated by bacterial enzymes to produce reactive molecules, and antibiotics such as aminoglycosides that corrupt, rather than merely inhibit, their targets. Some of these mechanisms are highly sophisticated, such as the preformed β-strands of darobactins that target the undruggable β-barrel chaperone BamA, or teixobactin, which binds to a precursor of peptidoglycan and then forms a supramolecular structure that damages the membrane, impeding the emergence of resistance. Many of the compounds exhibit more than one notable feature, such as resistance evasion and target corruption. Understanding the surprising complexity of the best antimicrobial compounds provides a roadmap for developing novel compounds to address the antimicrobial resistance crisis by mining for new natural products and inspiring us to design similarly sophisticated antibiotics.

Date: 2024
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-024-07530-w Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:632:y:2024:i:8023:d:10.1038_s41586-024-07530-w

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-024-07530-w

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().