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A Strategic Target Rescues Trimethoprim Sensitivity in Escherichia coli

Bhosle, A and Datey, A and Chandrasekharan, G and Singh, D and Chakravortty, D and Chandra, N (2020) A Strategic Target Rescues Trimethoprim Sensitivity in Escherichia coli. In: iScience, 23 (4).

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Official URL: https://dx.doi.org/10.1016/j.isci.2020.100986

Abstract

Trimethoprim, a preferred treatment for urinary tract infections, is becoming obsolete owing to the rapid dissemination of resistant E. coli. Although direct resistance mechanisms such as overexpression of a mutant FolA and dfr enzymes are well characterized, associated alterations that drive or sustain resistance are unknown. We identify the repertoire of resistance-associated perturbations by constructing and interrogating a transcriptome-integrated functional interactome. From the cross talk between perturbations in stress-response and metabolic pathways, we identify the critical dependence on serine hydroxymethyltransferase (GlyA) as an emergent vulnerability. Through its deletion, we demonstrate that GlyA is necessary to sustain high levels of resistance in both laboratory-evolved resistant E. coli and a multidrug-resistant clinical isolate. Through comparative evolution, we show that the absence of GlyA activity decelerates the acquisition of resistance in E. coli. Put together, our results identify GlyA as a promising target, providing a basis for the rational design of drug combinations.

Item Type: Journal Article
Additional Information: The copyright of this article belongs to CELL PRESS
Department/Centre: Division of Biological Sciences > Biochemistry
Division of Biological Sciences > Microbiology & Cell Biology
Division of Interdisciplinary Research > Centre for Biosystems Science and Engineering
Depositing User: Id for Latest eprints
Date Deposited: 18 Jun 2020 07:05
Last Modified: 18 Jun 2020 07:05
URI: http://eprints.iisc.ac.in/id/eprint/65047

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