Neutral metallated and meso-substituted porphyrins as antimicrobial agents against Gram-positive pathogens

Staphylococcus aureus is a bacterial pathogen that causes severe infections among humans. The increasing emergence of antibiotic resistance necessitates the development of new strategies to combat the spread of disease. One approach is photodynamic inactivation using porphyrin photosensitizers, which generate superoxide and other radicals in the presence of light, causing cell death via the oxidation of proteins and lipids. In this study, we analyzed a novel library of meso-substituted and metallated porphyrins for activity against multidrug-resistant S. aureus. From a library of 251 compounds, 51 showed antimicrobial activity, in three discrete classes of activity: those that functioned only in light, those that had toxicity only in darkness, and those that displayed activity regardless of illumination. We further demonstrated the broad-spectrum activity of these compounds against a variety of pathogens, including Bacillus anthracis, Enterococcus faecalis, and Escherichia coli. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) analyses of lead compounds (XPZ-263 and XPZ-271) revealed strong activity and killing towards methicillin-resistant S. aureus (MRSA) strains. An analysis of mutation frequencies revealed low incidences of resistance to lead compounds by E. coli and MRSA. Finally, an exploration of the underlying mechanism of action suggests that these compounds do not depend solely upon light-induced radical generation for toxicity, highlighting their potential for clinical applications.