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bioRxiv · 10.64898/2026.10.10.758198

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

Wolf, A. S.·Ndupu, R. O.·Alumasa, J. N.
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Abstract

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 mug/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.

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Wolf, A. S., Ndupu, R. O., Alumasa, J. N.. 2026-10-12. Isoindole-benzohydrazide derivative potentiates colistin activity to overcome resistance conferred by MCR-1 variants in Escherichia coli. https://doi.org/10.64898/2026.10.10.758198

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