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Non‐iron metalloporphyrins: potent antibacterial compounds that exploit haem/Hb uptake systems of pathogenic bacteria

A new group of potent antibacterial compounds, non‐iron metalloporphyrins (MPs), is described. MPs possess a strong antibacterial activity against Gram‐positive bacteria, Gram‐negative bacteria and mycobacteria. Anaerobically grown bacteria and microorganisms that do not respire and/or express haem uptake systems were resistant to MPs. Antibacterial activity of MPs was not affected by known antibiotic resistance mechanisms operating in bacteria. The most potent MP against Y. enterocolitica, methicillin‐resistant S. aureus and M. smegmatis was gallium protoporphyrin IX (Ga‐PPIX). When tested alone, Ga ions and metal‐free porphyrins had approximately 100‐fold higher minimum inhibitory concentration (MIC) values for these organisms. Ga‐PPIX was not degraded by MP‐sensitive bacteria, indicating that the whole molecule is responsible for antibacterial activity. MPs are antibacterial ‘Trojan horses’, as they exploit haem transport systems of Gram‐negative bacteria as portals of entry into the cell. Bacterial mutants in superoxide dismutases, catalases and stationary‐phase sigma factors were hypersensitive to Ga‐PPIX. The extreme sensitivity of sod mutants to MPs and the requirement for active respiration for MP activity suggests that these compounds stimulate the production of reactive oxygen radicals in bacteria. Ga‐PPIX was not toxic to primary human fibroblasts, several established cell lines and experimental animals at concentrations > 100‐fold higher than the MIC for sensitive bacteria.