Nanoparticulate β-Cyclodextrin with Gallium Tetraphenylporphyrin Demonstrates in Vitro and in Vivo Antimicrobial Efficacy against Mycobacteroides abscessus and Mycobacterium avium

The emergence of drug-resistant pathogens causes the greatest challenge for drug development research. Recently, gallium(III)-based compounds have received great attention as novel antimicrobial agents against drug-resistant pathogens. Here, we synthesized a new β-cyclodextrin Ga nanoparticle (CDGaTP) using Ga tetraphenylporphyrin (GaTP, a hemin analogue) and β-cyclodextrin. The newly synthesized nanoparticle was nontoxic and efficient at a single dose, showing sustained drug release for 15 days in vitro. CDGaTP's activity with transferrin or lactoferrin was tested, and synergism in activity was observed against nontuberculosis mycobacteria (NTM), Mycobacterium avium (M. avium), and Mycobacteroides abscessus. Human serum albumin (HSA) decreased the efficacy of both GaTP and CDGaTP in a concentration-dependent manner. The NTMs incubated with GaTP or CDGaTP significantly produced reactive oxygen species (ROS), indicating potential inhibition of antioxidant enzymes, such as catalase. The single-dose CDGaTP displayed a prolonged intracellular inhibitory activity in an in vitro macrophage infection model against both NTMs. In addition, CDGaTP, not GaTP, was effective in a murine lung M. avium infection model when delivered via intranasal administration. These results suggest that CDGaTP provides new opportunities for the development of gallium-porphyrin based antibiotics.