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

• DOI: 10.1021/acs.molpharmaceut.3c00223
• Publication Date: 2023-07-20T19:50:54Z
• Authors: Seoung-ryoung Choi; Geoffrey A. Talmon; Kenneth Hearne; Jennifer Woo; Vu L. Truong; Bradley E. Britigan; Prabagaran Naraya...
• Keywords: Combination therapy

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 heme pathways, aerobic respiration. Ga(NO3)3, an iron mimetic, disrupts elemental Here, we demonstrate enhanced activity combination GaPP and Ga(NO3)3 methicillin-resistant S. aureus (MRSA) under iron-limited conditions, small colony variants (SCV). This therapy demonstrated significant without inducing slow-growing SCV. We also observed that inhibited MRSA catalase but not above seen with alone. Neither nor alone or their dominant superoxide dismutase expressed (SodA) conditions examined. Intranasal administration two compounds improved drug biodistribution in lungs compared intraperitoneal administration. In murine lung infection model, increase survival decrease CFUs mice received intranasal untreated control receiving No drug-related toxicity was as assessed histologically spleen, lung, nasal cavity, kidney both single repeated doses 10 mg /Kg over 13 days. Our results strongly suggest excellent synergism potential be developed novel infections