Microbicidal Mechanisms for Light-Activated Molecular Nanomachines in Mycobacterium smegmatis : A Model for Pathogenic Bacteria

There is a global health crisis of antimicrobial resistance, with over a million deaths annually attributed to antimicrobial-resistant pathogens, and mycobacterial infections are a major cause of antimicrobial-resistant infections, leading to more deaths than any other single infectious agent. Notably, the rise of multidrug-resistant (MDR), extensively drug-resistant (XDR), and totally drug-resistant (TDR) strains of Mycobacterium tuberculosis led to higher mortality rates and challenge all existing antibiotic regimens. Light-activated molecular nanomachines (MNMs) represent a promising class of broad-spectrum antimicrobial agents that could help counter this rise in antimicrobial resistance. Addressing a key knowledge gap, this study explores the mechanisms of action for MNMs in Mycobacterium smegmatis , a surrogate model for pathogenic mycobacteria. We show that fast rotor MNMs kill up to 97% of M. smegmatis and co-localize with the bacteria as part of their mechanism of action. The ability to translate these observations to pathogenic mycobacteria was demonstrated by the ability of MNMs to kill 93.5% of M. tuberculosis under similar conditions. These findings suggest that MNMs may provide innovative sustainable antimicrobial agents for the treatment of drug-resistant mycobacterial infections.