Antibacterial activity of nonantibiotics is independent of standard antibiotics

MARIANA NOTO GUILLEN HTTPS://ORCID.ORG/0000-0001-7528-6777, CARMEN LI HTTPS://ORCID.ORG/0000-0001-5597-0715, BRITTANY ROSENER HTTPS://ORCID.ORG/0000-0002-1836-8503, AND AMIR MITCHELL HTTPS://ORCID.ORG/0000-0001-9376-3987 Authors Info & Affiliations

DOI: 10.1126/science.adk7368

Abstract

Numerous nonantibiotic drugs have potent antibacterial activity and can adversely impact the human microbiome. The mechanistic underpinning of this toxicity remains largely unknown. We investigated the antibacterial activity of 200 drugs using genetic screens with thousands of barcoded Escherichia coli knockouts. We analyzed 2 million gene-drug interactions underlying drug-specific toxicity. Network-based analysis of drug-drug similarities revealed that antibiotics clustered into modules consistent with the mode of action of their established classes, while nonantibiotics remained unconnected. Half of the nonantibiotics clustered into separate modules, potentially revealing shared and unexploited targets for novel antimicrobials. Analysis of efflux systems revealed they widely impact antibiotics and nonantibiotics alike, suggesting that the impact of nonantibiotics on antibiotic cross-resistance should be investigated closely in vivo.

https://www.science.org/doi/10.1126/science.adk7368