Combination Therapy with Gallium Protoporphyrin and Gallium Nitrate Exhibits Enhanced Antimicrobial Activity <i>In Vitro</i> and <i>In Vivo</i> against Methicillin-Resistant <i>Staphylococcus aureus</i>
Seoung‐ryoung Choi, Geoffrey A. Talmon, Kenneth Hearne, Jennifer Woo, Vu L. Truong, Bradley E. Britigan, Prabagaran Narayanasamy
Abstract
There is a major need for the development of new therapeutics to combat antibiotic-resistant Staphylococcus aureus . Recently, gallium (Ga)-based complexes have shown promising antimicrobial effects against various bacteria, including multidrug-resistant organisms, by targeting multiple heme/iron-dependent metabolic pathways. Among these, Ga protoporphyrin (GaPP) inhibits bacterial growth by targeting heme pathways, including aerobic respiration. Ga(NO 3 ) 3, an iron mimetic, disrupts elemental iron pathways. Here, we demonstrate the enhanced antimicrobial activity of the combination of GaPP and Ga(NO 3 ) 3 against methicillin-resistant S. aureus (MRSA) under iron-limited conditions, including small colony variants (SCV). This therapy demonstrated significant antimicrobial activity without inducing slow-growing SCV. We also observed that the combination of GaPP and Ga(NO 3 ) 3 inhibited the MRSA catalase but not above that seen with Ga(NO 3 ) 3 alone. Neither GaPP nor Ga(NO 3 ) 3 alone or their combination inhibited the dominant superoxide dismutase expressed (SodA) under the iron-limited conditions examined. Intranasal administration of the combination of the two compounds improved drug biodistribution in the lungs compared to intraperitoneal administration. In a murine MRSA lung infection model, we observed a significant increase in survival and decrease in MRSA lung CFUs in mice that received combination therapy with intranasal GaPP and Ga(NO 3 ) 3 compared to untreated control or mice receiving GaPP or Ga(NO 3 ) 3 alone. No drug-related toxicity was observed as assessed histologically in the spleen, lung, nasal cavity, and kidney for both single and repeated doses of 10 mg Ga /Kg of mice over 13 days. Our results strongly suggest that GaPP and Ga(NO 3 ) 3 in combination have excellent synergism and potential to be developed as a novel therapy for infections with S. aureus .