Isoindole-benzohydrazide derivative potentiates colistin activity to overcome resistance conferred by MCR-1 variants in Escherichia coli
- 1Miami University
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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BibTeX
@misc{wolf2026isoindolebenzohydrazide,
title = {{Isoindole-benzohydrazide derivative potentiates colistin activity to overcome resistance conferred by MCR-1 variants in Escherichia coli}},
author = {A. S. Wolf and R. O. Ndupu and J. N. Alumasa},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.10.758198},
url = {https://www.biorxiv.org/content/10.64898/2026.10.10.758198v1},
note = {CC BY-ND},
}
RIS
TY - UNPB
TI - Isoindole-benzohydrazide derivative potentiates colistin activity to overcome resistance conferred by MCR-1 variants in Escherichia coli
AU - A. S. Wolf
AU - R. O. Ndupu
AU - J. N. Alumasa
PY - 2026
DA - 2026/10/10
PB - bioRxiv
DO - 10.64898/2026.10.10.758198
UR - https://www.biorxiv.org/content/10.64898/2026.10.10.758198v1
AB - 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.
ER -