Antibiofilm and intracellular activity of manganese tetraphenyl porphyrin targeting nontuberculous mycobacterial manganese/heme metabolism

Nontuberculous mycobacteria (NTM) are emerging opportunistic pathogens that cause severe pulmonary and disseminated infections, particularly in immunocompromised individuals. Their intrinsic drug resistance and ability to form robust biofilms make treatment extremely challenging. Manganese (Mn) plays vital roles in microbial oxidative stress defense, enzymatic regulation, and virulence. Targeting manganese metabolism offers a novel therapeutic avenue against NTM. In this context, manganese tetraphenylporphyrin (MnTP) demonstrated remarkable antimicrobial activity against various Mycobacteroides abscessus (MAB) and M. avium (MAH) strains, with low MIC values indicating potent inhibition. MnTP effectively inhibited biofilm formation, significantly reducing adherence and extracellular polymeric matrix production. Furthermore, MnTP disrupted preformed biofilms, highlighting its dual preventive and therapeutic potential. Mechanistic studies revealed MnTP-induced accumulation of reactive oxygen species (ROS), leading to oxidative damage and cell death. MnTP also enhanced catalase activity, confirming weakening of bacterial antioxidant defenses. Notably, hemin treatment rescued MAB growth from MnTP-induced toxicity, suggesting the effect in heme metabolism. MnTP also reduced the intracellular growth of MAB. Overall, these findings emphasize the importance of Mn/heme metabolism in NTM survival and establish MnTP as a promising manganese-based therapeutic for combating drug-resistant NTM infections through multifaceted mechanisms.