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
-
- 10,834
- views
-
- 1,557
- downloads
-
- 22
- 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
-
- Cell Biology
- Microbiology and Infectious Disease
Zika virus (ZIKV) infection causes significant human disease that, with no approved treatment or vaccine, constitutes a major public health concern. Its life cycle entirely relies on the cytoplasmic fate of the viral RNA genome (vRNA) through a fine-tuned equilibrium between vRNA translation, replication, and packaging into new virions, all within virus-induced replication organelles (vROs). In this study, with an RNA interference (RNAi) mini-screening and subsequent functional characterization, we have identified insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) as a new host dependency factor that regulates vRNA synthesis. In infected cells, IGF2BP2 associates with viral NS5 polymerase and redistributes to the perinuclear viral replication compartment. Combined fluorescence in situ hybridization-based confocal imaging, in vitro binding assays, and immunoprecipitation coupled to RT-qPCR showed that IGF2BP2 directly interacts with ZIKV vRNA 3’ nontranslated region. Using ZIKV sub-genomic replicons and a replication-independent vRO induction system, we demonstrated that IGF2BP2 knockdown impairs de novo vRO biogenesis and, consistently, vRNA synthesis. Finally, the analysis of immunopurified IGF2BP2 complex using quantitative mass spectrometry and RT-qPCR revealed that ZIKV infection alters the protein and RNA interactomes of IGF2BP2. Altogether, our data support that ZIKV hijacks and remodels the IGF2BP2 ribonucleoprotein complex to regulate vRO biogenesis and vRNA neosynthesis.
-
- Microbiology and Infectious Disease
Bacillus velezensis is a species of Bacillus that has been widely investigated because of its broad-spectrum antimicrobial activity. However, most studies on B. velezensis have focused on the biocontrol of plant diseases, with few reports on antagonizing Salmonella Typhimurium infections. In this investigation, it was discovered that B. velezensis HBXN2020, which was isolated from healthy black pigs, possessed strong anti-stress and broad-spectrum antibacterial activity. Importantly, B. velezensis HBXN2020 did not cause any adverse side effects in mice when administered at various doses (1×107, 1×108, and 1×109 CFU) for 14 days. Supplementing B. velezensis HBXN2020 spores, either as a curative or preventive measure, dramatically reduced the levels of S. Typhimurium ATCC14028 in the mice’s feces, ileum, cecum, and colon, as well as the disease activity index (DAI), in a model of infection caused by this pathogen in mice. Additionally, supplementing B. velezensis HBXN2020 spores significantly regulated cytokine levels (Tnfa, Il1b, Il6, and Il10) and maintained the expression of tight junction proteins and mucin protein. Most importantly, adding B. velezensis HBXN2020 spores to the colonic microbiota improved its stability and increased the amount of beneficial bacteria (Lactobacillus and Akkermansia). All together, B. velezensis HBXN2020 can improve intestinal microbiota stability and barrier integrity and reduce inflammation to help treat infection by S. Typhimurium.
