Breaking antimicrobial resistance by disrupting extracytoplasmic protein folding
| Title: | Breaking antimicrobial resistance by disrupting extracytoplasmic protein folding |
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| Authors: | R Christopher D Furniss, Nikol Kaderabkova, Declan Barker, Patricia Bernal, Evgenia Maslova, Amanda AA Antwi, Helen E McNeil, Hannah L Pugh, Laurent Dortet, Jessica MA Blair, Gerald Larrouy-Maumus, Ronan R McCarthy, Diego Gonzalez, Despoina AI Mavridou |
| Source: | eLife, Vol 11 (2022) |
| Publisher Information: | eLife Sciences Publications Ltd, 2022. |
| Publication Year: | 2022 |
| Collection: | LCC:Medicine LCC:Science LCC:Biology (General) |
| Subject Terms: | antimicrobial resistance, disulfide bond formation, cell envelope, K. pneumoniae, P. aeruginosa, G. mellonella, Medicine, Science, Biology (General), QH301-705.5 |
| More Details: | 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. |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 2050-084X |
| Relation: | https://elifesciences.org/articles/57974; https://doaj.org/toc/2050-084X |
| DOI: | 10.7554/eLife.57974 |
| Access URL: | https://doaj.org/article/ef99dec094a54ce9adaa86f09bb26e0b |
| Accession Number: | edsdoj.f99dec094a54ce9adaa86f09bb26e0b |
| Database: | Directory of Open Access Journals |
| ISSN: | 2050084X |
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| DOI: | 10.7554/eLife.57974 |
| Published in: | eLife |
| Language: | English |