ZnuB as a targetable vulnerability to combat colistin resistance.

znuB loss in colistin-exposed bacteria markedly increases both bacteriostatic and bactericidal activity of colistin, linking zinc uptake to colistin sensitivity.

• Why it matters: Plasmid spread of mcr genes has weakened colistin, and metal-ion acquisition systems are not well explored as druggable vulnerabilities to restore its potency.
• What they did: The study used znuB deficiency to test colistin effects, then mapped mechanisms via leuO upregulation, ompS1/dsbI-linked membrane damage, oxidative stress, and diacylglycerol changes that inhibit MCR activity. It also screened farrerol and ajmaline as inhibitors of both ZnuB and MCR.
• The result: In murine infection models, colistin plus these inhibitors improved survival and lowered bacterial burdens, supporting zinc-homeostasis targeting as a strategy to reverse colistin resistance.

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