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.
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.
Metrics
-
- 11,203
- views
-
- 1,607
- downloads
-
- 25
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Breaking antimicrobial resistance by disrupting extracytoplasmic protein folding
eLife 11:e57974.
https://doi.org/10.7554/eLife.57974
Further reading
-
- Computational and Systems Biology
- Microbiology and Infectious Disease
Antimicrobial peptides (AMPs) are attractive candidates to combat antibiotic resistance for their capability to target biomembranes and restrict a wide range of pathogens. It is a daunting challenge to discover novel AMPs due to their sparse distributions in a vast peptide universe, especially for peptides that demonstrate potencies for both bacterial membranes and viral envelopes. Here, we establish a de novo AMP design framework by bridging a deep generative module and a graph-encoding activity regressor. The generative module learns hidden ‘grammars’ of AMP features and produces candidates sequentially pass antimicrobial predictor and antiviral classifiers. We discovered 16 bifunctional AMPs and experimentally validated their abilities to inhibit a spectrum of pathogens in vitro and in animal models. Notably, P076 is a highly potent bactericide with the minimal inhibitory concentration of 0.21 μM against multidrug-resistant Acinetobacter baumannii, while P002 broadly inhibits five enveloped viruses. Our study provides feasible means to uncover the sequences that simultaneously encode antimicrobial and antiviral activities, thus bolstering the function spectra of AMPs to combat a wide range of drug-resistant infections.
-
- Microbiology and Infectious Disease
Mycobacterium tuberculosis (Mtb) infection of macrophages reprograms cellular metabolism to promote lipid retention. While it is clearly known that intracellular Mtb utilize host-derived lipids to maintain infection, the role of macrophage lipid processing on the bacteria’s ability to access the intracellular lipid pool remains undefined. We utilized a CRISPR-Cas9 genetic approach to assess the impact of sequential steps in fatty acid metabolism on the growth of intracellular Mtb. Our analyses demonstrate that macrophages that cannot either import, store, or catabolize fatty acids restrict Mtb growth by both common and divergent antimicrobial mechanisms, including increased glycolysis, increased oxidative stress, production of pro-inflammatory cytokines, enhanced autophagy, and nutrient limitation. We also show that impaired macrophage lipid droplet biogenesis is restrictive to Mtb replication, but increased induction of the same fails to rescue Mtb growth. Our work expands our understanding of how host fatty acid homeostasis impacts Mtb growth in the macrophage.
