The cell envelope of bacteria as a target for chelant and antibiotic combinations

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Bacterial metal and antibiotic resistance are increasingly recognised as processes that evolve in parallel. Although not well-characterised, co-resistance is frequently associated with cellular import and export mechanisms. Indeed, some antibiotics are actively transported to their intracellular targets as metal complexes. Hence disrupting the uptake of both metals and antibiotics, either separately or together, offers significant potential to combat increasingly drug-resistant pathogens. This project emerges from successful efforts, in partnership with Procter & Gamble, to deprive bacterial pathogens of essential metals using metal chelants with differing selectivities. To help determine the mode of action of two chelants with affinities for different metallic species, we isolated chelant-resistant mutants of two bacterial species and identified chromosomal changes from the resulting strains. Several mutations were found that affected the anticipated metal uptake systems. However, additional mutations were identified that altered cell surface molecules, membrane-bound transporters and enzymes engaged in peptidoglycan metabolism. Interestingly, improved resistance to certain antibiotics was also evident in several of the mutants. Moreover, treating bacteria with combinations of chelants and antibiotics identified synergistic, additive and indifferent effects. The wild-type and mutant derivatives of these bacteria therefore provide an excellent opportunity to probe the relationship between antibiotics, metal chelation and cell envelope integrity. This project aims to understand how chelants and antibiotics target and traverse the bacterial envelope and explore links with metal uptake and tolerance. There are significant prospects commercially for improving product formulations through a better understanding of how chelants inhibit bacterial growth. Furthermore, it offers the potential to revitalise existing antibiotics for topical applications in the treatment of wounds, in both medical and veterinary contexts, caused by important antibiotic-resistant pathogens.