Breaking antimicrobial resistance by disrupting extracytoplasmic protein folding
- Imperial College London, United Kingdom
- The University of Texas at Austin, United States
- Universidad de Sevilla, Spain
- Brunel University London, United Kingdom
- University of Birmingham, United Kingdom
- Paris-Sud University, France
- University of Neuchatel, Switzerland
Abstract
Antimicrobial resistance in Gram-negative bacteria is one of the greatest threats to global health. New antibacterial strategies are urgently needed, and the development of antibiotic adjuvants that either neutralize resistance proteins or compromise the integrity of the cell envelope is of ever-growing interest. Most available adjuvants are only effective against specific resistance proteins. Here we demonstrate that disruption of cell envelope protein homeostasis simultaneously compromises several classes of resistance determinants. In particular, we find that impairing DsbA-mediated disulfide bond formation incapacitates diverse β-lactamases and destabilizes mobile colistin resistance enzymes. Furthermore, we show that chemical inhibition of DsbA sensitizes multidrug-resistant clinical isolates to existing antibiotics and that the absence of DsbA, in combination with antibiotic treatment, substantially increases the survival of Galleria mellonella larvae infected with multidrug-resistant Pseudomonas aeruginosa. This work lays the foundation for the development of novel antibiotic adjuvants that function as broad-acting resistance breakers.
Data availability
All data generated during this study that support the findings are included in the manuscript or in the Supplementary Information.
Article and author information
Author details
Despoina AI Mavridou
Funding
Medical Research Council (MR/M009505/1)
- Despoina AI Mavridou
Swiss National Science Foundation (PZ00P3_180142)
- Diego Gonzalez
Academy of Medical Sciences (SBF006\1040)
- Ronan R McCarthy
National Institutes of Health (R01AI158753)
- Despoina AI Mavridou
Biotechnology and Biological Sciences Research Council (BB/M02623X/1)
- Jessica MA Blair
Wellcome Trust (105603/Z/14/Z)
- Gerald J Larrouy-Maumus
British Society for Antimicrobial Chemotherapy (BSAC-2018-0095)
- Ronan R McCarthy
Biotechnology and Biological Sciences Research Council (BB/V007823/1)
- Ronan R McCarthy
Swiss National Science Foundation (P300PA_167703)
- Diego Gonzalez
NC3Rs (NC/V001582/1)
- Ronan R McCarthy
Biotechnology and Biological Sciences Research Council (BB/M011178/1)
- Nikol Kaderabkova
Biotechnology and Biological Sciences Research Council (BB/M01116X/1)
- Hannah L Pugh
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Melanie Blokesch, Ecole Polytechnique Fédérale de Lausanne, Switzerland
Version history
- Received: May 19, 2020
- Preprint posted: August 28, 2021 (view preprint)
- Accepted: January 11, 2022
- Accepted Manuscript published: January 13, 2022 (version 1)
- Version of Record published: February 22, 2022 (version 2)
Copyright
© 2022, Furniss et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Breaking antimicrobial resistance by disrupting extracytoplasmic protein folding
eLife 11:e57974.
https://doi.org/10.7554/eLife.57974
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