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Title: Breaking antimicrobial resistance by disrupting extracytoplasmic protein folding
Authors: Furniss, RCD
Kaderabkova, N
Barker, D
Bernal, P
Maslova, E
Antwi, AAA
McNeil, HE
Pugh, HL
Dortet, L
Blair, JMA
Larrouy-Maumus, GJ
McCarthy, RR
Gonzalez, D
Mavridou, DAI
Issue Date: 13-Jan-2022
Publisher: eLife Sciences Publications, Ltd
Citation: Furniss, R.C.D., Kaderabkova, N., Barker, D., Bernal, P., Maslova, E., Antwi, A.A.A., McNeil, H.E., Pugh, H.L., Dortet, L., Blair, J.M.A., Larrouy-Maumus, G,J., McCarthy, R.R., Gonzalez, D. and Mavridou, D.A.I. (2022) 'Breaking antimicrobial resistance by disrupting extracytoplasmic protein folding', eLife, 11, e57974, pp. 1-69. doi: 10.7554/elife.57974.
Abstract: Copyright © 2022, Furniss et al. 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.
Description: Data availability: All data generated during this study that support the findings are included in the manuscript or in the Supplementary Information.
Other Identifiers: e57974
Appears in Collections:Dept of Life Sciences Research Papers

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