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.
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Breaking antimicrobial resistance by disrupting extracytoplasmic protein folding
eLife 11:e57974.
https://doi.org/10.7554/eLife.57974
Further reading
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- Medicine
- Microbiology and Infectious Disease
Background:
Under which conditions antibiotic combination therapy decelerates rather than accelerates resistance evolution is not well understood. We examined the effect of combining antibiotics on within-patient resistance development across various bacterial pathogens and antibiotics.
Methods:
We searched CENTRAL, EMBASE, and PubMed for (quasi)-randomised controlled trials (RCTs) published from database inception to 24 November 2022. Trials comparing antibiotic treatments with different numbers of antibiotics were included. Patients were considered to have acquired resistance if, at the follow-up culture, a resistant bacterium (as defined by the study authors) was detected that had not been present in the baseline culture. We combined results using a random effects model and performed meta-regression and stratified analyses. The trials’ risk of bias was assessed with the Cochrane tool.
Results:
42 trials were eligible and 29, including 5054 patients, qualified for statistical analysis. In most trials, resistance development was not the primary outcome and studies lacked power. The combined odds ratio for the acquisition of resistance comparing the group with the higher number of antibiotics with the comparison group was 1.23 (95% CI 0.68–2.25), with substantial between-study heterogeneity (I2=77%). We identified tentative evidence for potential beneficial or detrimental effects of antibiotic combination therapy for specific pathogens or medical conditions.
Conclusions:
The evidence for combining a higher number of antibiotics compared to fewer from RCTs is scarce and overall compatible with both benefit or harm. Trials powered to detect differences in resistance development or well-designed observational studies are required to clarify the impact of combination therapy on resistance.
Funding:
Support from the Swiss National Science Foundation (grant 310030B_176401 (SB, BS, CW), grant 32FP30-174281 (ME), grant 324730_207957 (RDK)) and from the National Institute of Allergy and Infectious Diseases (NIAID, cooperative agreement AI069924 (ME)) is gratefully acknowledged.
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- Evolutionary Biology
- Microbiology and Infectious Disease
The global rise of antibiotic resistance calls for new drugs against bacterial pathogens. A common approach is to search for natural compounds deployed by microbes to inhibit competitors. Here, we show that the iron-chelating pyoverdines, siderophores produced by environmental Pseudomonas spp., have strong antibacterial properties by inducing iron starvation and growth arrest in pathogens. A screen of 320 natural Pseudomonas isolates used against 12 human pathogens uncovered several pyoverdines with particularly high antibacterial properties and distinct chemical characteristics. The most potent pyoverdine effectively reduced growth of the pathogens Acinetobacter baumannii, Klebsiella pneumoniae, and Staphylococcus aureus in a concentration- and iron-dependent manner. Pyoverdine increased survival of infected Galleria mellonella host larvae and showed low toxicity for the host, mammalian cell lines, and erythrocytes. Furthermore, experimental evolution of pathogens combined with whole-genome sequencing revealed limited resistance evolution compared to an antibiotic. Thus, pyoverdines from environmental strains have the potential to become a new class of sustainable antibacterials against specific human pathogens.
