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 in Escherichia 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 of E. coli without a separate fitness cost. These fitness neutral gene perturbations worked as co-therapies in reducing a Salmonella enterica intracellular infection in HeLa. Finally, these results informed the design of four antisense peptide nucleic acid (PNA) co-therapies, csgD, fnr, recA and acrA, against four MDR, clinically isolated bacteria. PNA combined with sub-minimal inhibitory concentrations of trimethoprim against two isolates of Klebsiella pneumoniae and E. coli showed three cases of re-sensitization with minimal fitness impacts. Our results highlight a promising approach for extending the utility of current antibiotics.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Nov 05, 2021
- Source ID
- 10.1038/s42003-021-02783-x
Entities
People
- Anushree Chatterjee
- Jocelyn Campos
- Keesha E Erickson
- Kristen A. Eller
- Peter B. Otoupal
- Thomas R Aunins
Organizations
- National Science Foundation
- United States Department of Defense