Macrophages and other immune cells manipulate the cellular distribution of zinc as an antimicrobial defence strategy, directing toxic concentrations of this biometal towards intracellular pathogens in a process known as metal ion poisoning. Manipulating this zinc toxicity pathway offers a potential strategy to enhance host defence and overcome antimicrobial resistant (AMR) infections. This response is coordinated by a network of zinc transporters, including SLC30A1, which also constrains hepatic inflammation-driven pathology. In macrophages from people with cystic fibrosis (pwCF), SLC30A1 expression is attenuated, and the zinc toxicity response is impaired. Therapies that restore SLC30A1 expression may therefore have potential as host-directed therapies (HDTs) to combat AMR pathogens in pwCF and other groups who are also vulnerable to infections, for example people with chronic liver disease (pwCLD). Here, we investigated the mechanisms of zinc toxicity against bacterial pathogens and explored SLC30A1 mRNA delivery as a strategy to both promote zinc-mediated bacterial clearance and reduce inflammation-mediated pathology. Pathogenic E. coli sequence type 95 (ST95) and M. abscessus, two bacterial pathogens of particular concern to pwCLD and pwCF, respectively, were susceptible to zinc poisoning. Mechanistically, culture conditions that mimicked some aspects of the macrophage phagosome sensitised E. coli ST95 to zinc poisoning, with magnesium deprivation being particularly important for this effect. To develop strategies to boost the zinc toxicity response, mRNA-mediated delivery of functional SLC30A1 protein to human macrophages was established. Current studies are investigating the effects of SLC30A1 mRNA delivery on antimicrobial and inflammatory responses in macrophages. The effects of mRNA delivery of the divalent metal ion transporter and magnesium exporter, NRAMP1, to further enhance this zinc toxicity pathway are also being explored. Findings to date offer insights into mechanisms underlying the zinc toxicity response and provide a foundation for developing HDTs that enhance innate immune defence to combat AMR bacterial pathogens.