Dual Inhibition of Klebsiella pneumoniae and Pseudomonas aeruginosa Iron Metabolism using Gallium Porphyrin and Gallium Nitrate

Iron- and heme-uptake pathways and metabolism are promising targets for the development of new antimicrobial agents, as their disruption would lead to nutritional iron starvation and inhibition of bacterial growth. Salts of gallium III (Ga), an iron mimetic metal, disrupt iron-dependent biological processes by binding iron-utilizing proteins and compete with iron for uptake by bacterial siderophore-mediated iron uptake systems. Ga porphyrins, heme mimetic complexes, disrupt heme-utilizing hemeproteins. Because Ga(NO3)3 and Ga porphyrin disrupt different pathways of bacterial ion acquisition/utilization, we hypothesized that if used in combination they would result in enhanced antimicrobial activity. Antimicrobial activity of Ga porphyrins (Ga protoporphyrin (GaPP) or Ga mesoporphyrin (GaMP)) alone and in combination with Ga(NO3)3 were evaluated against Pseudomonas aeruginosa, Klebsiella pneumoniae, Acinetobacter baumannii, and methicillin-resistant Staphylococcus aureus (MRSA) under iron-limited condition...