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2026 Poster Session C

C09 - Elucidating the Mechanism of Resistance to β-lactam Antibiotics Conferred by a Variant of the Mobilized Colistin Resistance Enzyme (MCR-1-M6)

Antibiotic resistance is an urgent global public health crisis, projected to cause about 50 million annual fatalities by 2050.

2026 Poster Session C

C09 - Elucidating the Mechanism of Resistance to β-lactam Antibiotics Conferred by a Variant of the Mobilized Colistin Resistance Enzyme (MCR-1-M6)

Mentor: John Alumasa, Ph.D./

Antibiotic resistance is an urgent global public health crisis, projected to cause about 50 million annual fatalities by 2050. Bacterial enzymes play a crucial role in promoting this phenomenon, complicating efforts to combat fatal infections. The plasmid-localized mcr-1 gene encodes an enzyme that confers resistance to colistin, a last-resort antibiotic used to treat deadly multidrug-resistant Enterobacteriaceae infections. MCR-1 confers resistance by covalently modifying lipopolysaccharides (LPS) with a positively charged phosphoethanolamine (PEA) moiety, derived from phosphatidylethanolamine (PE). This transformation neutralizes the membrane charge, preventing binding by colistin, a cationic polypeptide antibiotic. MCR-1 catalysis requires two Zn2+ ions as cofactors; one facilitating cleavage of PEA in the first step, and the other involved in its conjugation onto lipid A in the second step. This work sought to identify MCR-1 inhibitors to restore colistin activity against Gram-negative pathogens. Computer-aided virtual screening was used to identify small molecules predicted to bind with high affinity to the substrate- or cofactor-binding regions. Cell-based screens against MCR-1-expressing Escherichia coli cells revealed no independent antibacterial activity by the test compounds. Combinations of colistin with these compounds identified a promising indol-benzohydrazide derivative, JNAL-042, which displayed strong antibiotic-adjuvant properties. This compound restored colistin’s activity in resistant cells expressing MCR-1. Fluorescence-based time-kill reporter assays displayed no MCR-1-mediated resistance to colistin 7 hours post-treatment in the presence of JNAL-042. Computational docking predicted binding of JNAL-042 near the lipid A-binding site, suggesting potential interference with the second catalytic step, involving the Zn2+-dependent transfer of PEA onto LPS. Preliminary in vitro experiments with purified MCR-1 supported this hypothesis, demonstrating that JNAL-042 did not inhibit PE cleavage. Ongoing experiments seek to validate MCR-1 as the biological target of JNAL-042 and elucidate the molecular mechanism of enzyme inhibition using site-directed mutagenesis. Collectively, our findings offer a promising strategy employing antibiotic adjuvants to tackle MCR-1-mediated resistance and secure the clinical use of colistin as a last-resort antibiotic against multidrug-resistant pathogens.

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