Microbicidal mechanisms for light-activated molecular nanomachines in Mycobacterium smegmatis: A model for pathogenic...

There is a global health crisis of antimicrobial resistance, responsible for over a million deaths annually. Mycobacterial infections are a major contributor to this crisis, causing 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 has 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 significantly reduce bacterial viability, achieving up to 97 % reduction in M. smegmatis with 30 minutes of light activation when compared to non-activated MNM 1 (p < 0.0001, t = 24.55), as determined by an unpaired t-test. Using fluorescence and confocal microscopy, we also show the colocalization of MNM 1 with M. smegmatis as part of their mechanism of action. The ability to translate these observations to pathogenic mycobacteria was demonstrated by the ability of MNM 1 to kill 93.5 % of M. tuberculosis with 5 minutes of light activation when compared to non-activated MNM 1 (p < 0.0001, t = 19.24). These findings suggest that MNMs have the potential to be innovative and sustainable antimicrobial agents for the treatment of pathogenic mycobacterial infections.