Isoindole-benzohydrazide derivative potentiates colistin activity to overcome resistance conferred by MCR-1 variants in Escherichia coli

Polymyxin antibiotic resistance mediated by the mobilized colistin resistance (MCR) enzyme threatens the last-resort treatment of deadly multidrug-resistant pathogens, including Acinetobacter baumannii, and calls for urgent mitigation efforts. We used a multifaceted approach involving computational and wet-lab techniques to identify an isoindole-benzohydrazide derivative, JNAL-042, which potentiates colistin activity in an Escherichia coli MCR-resistance phenotype screening model. JNAL-042 lacked intrinsic antibiotic activity but potentiated that of polymyxin antibiotics at 12-24 µg/ml, as demonstrated by bacterial growth susceptibility screens. Cell viability counts and time-kill assays corroborated these findings, demonstrating complete abolition of MCR-mediated resistance by the antibiotic-adjuvant combination at concentrations mirroring those of empty vector controls. Post-induction treatment with this combination similarly prevented the propagation of the resistance phenotype, albeit at a higher antibiotic dose. This landmark study presents JNAL-042 as a promising antibiotic adjuvant to combat MCR-mediated resistance and offers a viable solution to preserve last-resort polymyxin antibiotics.