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Title: Potentiating antibiotic efficacy via perturbation of non-essential gene expression
Abstract Proliferation of multidrug-resistant (MDR) bacteria poses a threat to human health, requiring new strategies. Here we propose using fitness neutral gene expression perturbations to potentiate antibiotics. We systematically explored 270 gene knockout-antibiotic combinations inEscherichia coli, identifying 90 synergistic interactions. Identified gene targets were subsequently tested for antibiotic synergy on the transcriptomic level via multiplexed CRISPR-dCas9 and showed successful sensitization ofE. coliwithout a separate fitness cost. These fitness neutral gene perturbations worked as co-therapies in reducing aSalmonella entericaintracellular infection in HeLa. Finally, these results informed the design of four antisense peptide nucleic acid (PNA) co-therapies,csgD,fnr,recAandacrA, against four MDR, clinically isolated bacteria. PNA combined with sub-minimal inhibitory concentrations of trimethoprim against two isolates ofKlebsiella pneumoniaeandE. colishowed three cases of re-sensitization with minimal fitness impacts. Our results highlight a promising approach for extending the utility of current antibiotics.  more » « less
Award ID(s):
1714564
PAR ID:
10304684
Author(s) / Creator(s):
; ; ; ; ;
Publisher / Repository:
Nature Publishing Group
Date Published:
Journal Name:
Communications Biology
Volume:
4
Issue:
1
ISSN:
2399-3642
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
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