Discovery of Broad-Spectrum Repurposed Drug Combinations Against Carbapenem-Resistant <i>Enterobacteriaceae</i> (CRE) Through Artificial Intelligence (AI)-Driven Platform

Abstract

Antimicrobial resistance challenges the sustainability of healthcare systems and results in substantial economic losses worldwide. This issue is further aggravated by paucity of new drugs and treatment options. In this study, an artificial intelligence (AI)-derived platform termed IDentif.AI is utilized to accelerate the development of effective therapeutic options for carbapenem-resistant Enterobacteriaceae (CRE). Twelve Food and Drug Administration-approved drugs are selected and the in vitro inhibitory efficacy of 155 combinations consisting of various drugs is determined at different concentrations against both Klebsiella pneumoniae and Escherichia coli. Correlating these experimental data via an AI-derived relationship, IDentif.AI rapidly determines a ranked list of drug combinations in the search space of over half a million possible combinations. Meropenem is found to strongly synergize with low doses of the anticancer drug bleomycin, showing broad-spectrum, bactericidal activity against nine isolates across three CRE species in rich and minimal media with no synergistic cytotoxicity on mammalian cells. Synergy is also detected between bleomycin and other key carbapenems in clinical use (imipenem, ertapenem). Bleomycin/carbapenem appears to be a promising combination therapy for treating various CRE infections. IDentif.AI shows profound capability of identifying pan-active drug combinations against a family of bacteria through surveying strains from different species in parallel.