Issue 36, 2021

A novel chemical biology and computational approach to expedite the discovery of new-generation polymyxins against life-threatening Acinetobacter baumannii

Abstract

Multidrug-resistant Gram-negative bacteria represent a major medical challenge worldwide. New antibiotics are desperately required with ‘old’ polymyxins often being the only available therapeutic option. Here, we systematically investigated the structure–activity relationship (SAR) of polymyxins using a quantitative lipidomics-informed outer membrane (OM) model of Acinetobacter baumannii and a series of chemically synthesized polymyxin analogs. By integrating chemical biology and all-atom molecular dynamics simulations, we deciphered how each residue of the polymyxin molecule modulated its conformational folding and specific interactions with the bacterial OM. Importantly, a novel designed polymyxin analog FADDI-287 with predicted stronger OM penetration showed improved in vitro antibacterial activity. Collectively, our study provides a novel chemical biology and computational strategy to expedite the discovery of new-generation polymyxins against life-threatening Gram-negative ‘superbugs’.

Graphical abstract: A novel chemical biology and computational approach to expedite the discovery of new-generation polymyxins against life-threatening Acinetobacter baumannii

Supplementary files

Article information

Article type
Edge Article
Submitted
25 Jun 2021
Accepted
12 Aug 2021
First published
19 Aug 2021
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2021,12, 12211-12220

A novel chemical biology and computational approach to expedite the discovery of new-generation polymyxins against life-threatening Acinetobacter baumannii

X. Jiang, N. A. Patil, M. A. K. Azad, H. Wickremasinghe, H. Yu, J. Zhao, X. Zhang, M. Li, B. Gong, L. Wan, W. Ma, P. E. Thompson, K. Yang, B. Yuan, F. Schreiber, L. Wang, T. Velkov, K. D. Roberts and J. Li, Chem. Sci., 2021, 12, 12211 DOI: 10.1039/D1SC03460J

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