Breaking antimicrobial resistance by disrupting extracytoplasmic protein folding

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 J Larrouy-Maumus, Ronan R McCarthy, Diego Gonzalez, Despoina Ai Mavridou

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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.

Original languageEnglish
Article numbere57974
JournaleLife
Volume11
DOIs
Publication statusPublished - 13 Jan 2022

Bibliographical note

Funding:
This work was supported by NIH grants AI138709 (PI JMO) and AI146028 (PI FAM). JMO received support as the Endowed Chair for Graduate Education (FHCRC). The research of FAM was supported in part by a Faculty Scholar grant from the Howard Hughes Medical Institute and the Simons Foundation. Scientific Computing Infrastructure at Fred Hutch was funded by ORIP grant S10OD028685.

Keywords

  • E. coli
  • infectious disease
  • microbiology

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)

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