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.
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Acknowledgements
K.L. is supported by US National Institutes of Health grants (RO1 AI170962 and R01 AI158388), The Schmidt Foundation and The Steven and Alexandra Cohen Foundation. R.E.L. is supported by US National Institutes of Health grants (AI141193, AI090810 and AI157312) and ALSAC, St Jude’s Children Research Hospital. H.B.O. is grateful for funding by the Deutsche Forschungsgemeinschaft (German Research Foundation) TRR261 (project ID 398967434) and CoE CMFI (390838134). This project was supported by the Swiss National Science Foundation via the NCCR AntiResist (grant number 180541) to S.H. T.S. is supported by the German Center for Infection Research (DZIF), the Deutsche Forschungsgemeinschaft (German Research Foundation) TRR261 (project ID 398967434) and GRK2873 (project ID 494832089). We acknowledge funding by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 101045485 to M.W.). This work was supported by the Deutsche Forschungsgemeinschaft (German Research Foundation) grants SFB1565 (project ID 469281184) to M.V.R. and I.W., by the Leibniz Prize to M.V.R. and by the Max Planck Society. The authors thank L. Wilt, S. Anderson and R. Tangallapally for their assistance in preparing this review.
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K.L., R.E.L., H.B.O., S.H., M.V.R., T.S., M.W. and I.W. conceived and wrote this review.
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K.L. is a consultant for NovoBiotic, Arietis, Odyssey Therapeutics, Holobiome, Donum and Flightpath. R.E.L. is an advisor for Prokaryotics and is a co-inventor of relevant intellectual property licensed by Arietis and Microbiotix. H.B.O. S.H., M.V.R., T.S., M.W. and I.W. declare no competing interests
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Supplementary Table 1
An alphabetical listing of all discussed antibiotics and their corresponding chemical structures.
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Lewis, K., Lee, R.E., Brötz-Oesterhelt, H. et al. Sophisticated natural products as antibiotics. Nature 632, 39–49 (2024). https://doi.org/10.1038/s41586-024-07530-w
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DOI: https://doi.org/10.1038/s41586-024-07530-w
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