Breaking antimicrobial resistance by disrupting extracytoplasmic protein folding

• Published in: eLife Vol. 11
• Main Authors: Furniss, R Christopher D, Kaderabkova, Nikol, Barker, Declan, Bernal, Patricia, Maslova, Evgenia, Antwi, Amanda A A, McNeil, Helen E, Pugh, Hannah L, Dortet, Laurent, Blair, Jessica M A, Larrouy-Maumus, Gerald, McCarthy, Ronan R, Gonzalez, Diego, Mavridou, Despoina A I
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 13.01.2022; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Adjuvants; Adjuvants, Pharmaceutic; Animals; Anti-Bacterial Agents - therapeutic use; Antibacterial agents; Antibiotics; Antimicrobial agents; Antimicrobial resistance; Bacteria; beta-Lactamases - genetics; beta-Lactamases - metabolism; cell envelope; Chemical bonds; Clinical isolates; Colistin; disulfide bond formation; Drug resistance; Drug resistance in microorganisms; Drug Resistance, Multiple, Bacterial; E coli; Enzymes; Experiments; G. mellonella; Gene Expression Regulation, Bacterial - drug effects; Gene Expression Regulation, Enzymologic; Genes, Bacterial; Gram-negative bacteria; Health aspects; Homeostasis; K. pneumoniae; Larva - microbiology; Microbial Sensitivity Tests; Microbiology and Infectious Disease; Moths - microbiology; Multidrug resistance; P. aeruginosa; Phylogenetics; Protein Folding; Pseudomonas aeruginosa - drug effects; Public health; Viral envelope proteins; Virulence; World health; β Lactamase; Canada; K. pneumoniae; antimicrobial resistance; infectious disease; cell envelope; disulfide bond formation; microbiology; G. mellonella; E. coli; P. aeruginosa
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.57974

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 larvae infected with multidrug-resistant . This work lays the foundation for the development of novel antibiotic adjuvants that function as broad-acting resistance breakers.