Combination Therapy with Gallium Protoporphyrin and Gallium Nitrate Exhibits Enhanced Antimicrobial Activity In Vitro and In Vivo against Methicillin-Resistant Staphylococcus aureus

There is a major need for the development of new therapeuticstocombat antibiotic-resistant Staphylococcus aureus. Recently, gallium (Ga)-based complexes have shown promising antimicrobialeffects against various bacteria, including multidrug-resistant organisms,by targeting multiple heme/iron-dependent metabolic pathways. Amongthese, Ga protoporphyrin (GaPP) inhibits bacterial growth by targetingheme pathways, including aerobic respiration. Ga(NO3)(3), an iron mimetic, disrupts elemental iron pathways. Here,we demonstrate the enhanced antimicrobial activity of the combinationof GaPP and Ga(NO3)(3) against methicillin-resistant S. aureus (MRSA) under iron-limited conditions, includingsmall colony variants (SCV). This therapy demonstrated significantantimicrobial activity without inducing slow-growing SCV. We alsoobserved that the combination of GaPP and Ga(NO3)(3) inhibited the MRSA catalase but not above that seen with Ga(NO3)(3) alone. Neither GaPP nor Ga(NO3)(3) alone or their combination inhibited the dominant superoxidedismutase expressed (SodA) under the iron-limited conditions examined.Intranasal administration of the combination of the two compoundsimproved drug biodistribution in the lungs compared to intraperitonealadministration. In a murine MRSA lung infection model, we observeda significant increase in survival and decrease in MRSA lung CFUsin mice that received combination therapy with intranasal GaPP andGa(NO3)(3) compared to untreated control or micereceiving GaPP or Ga(NO3)(3) alone. No drug-relatedtoxicity was observed as assessed histologically in the spleen, lung,nasal cavity, and kidney for both single and repeated doses of 10mg Ga /Kg of mice over 13 days. Our results strongly suggest thatGaPP and Ga(NO3)(3) in combination have excellentsynergism and potential to be developed as a novel therapy for infectionswith S. aureus.