Open AccessBreaking antimicrobial resistance by disrupting extracytoplasmic protein folding
Author(s) -
R. Christopher D. Furniss,
Nikol Kadeřábková,
Declan Barker,
Patricia Bernal,
Evgenia Maslova,
Amanda AA Antwi,
Helen E McNeil,
Hannah L Pugh,
Laurent Dortet,
Jessica M A Blair,
Gérald Larrouy-Maumus,
Ronan R. McCarthy,
Diego González,
Despoina A. I. Mavridou
Publication year - 2022
Publication title -
elife
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.879
H-Index - 139
ISSN - 2050-084X
DOI - 10.7554/elife.59046
Subject(s) - antibiotic resistance , microbiology and biotechnology , antibiotics , biology , biofilm , pseudomonas aeruginosa , antimicrobial , multidrug tolerance , multiple drug resistance , dsba , acinetobacter baumannii , colistin , drug resistance , bacteria , biochemistry , escherichia coli , periplasmic space , genetics , gene
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.