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. Graphical AbstractBacteria exposed to MNMs have two distinct outcomes when activated by 365 nm light. Slow motors (MNM 2 and 4) have no rotational action, remains outside the bacteria and have little to no effect on bacterial viability. Whereas fast motors (MNM 1 and 3) co-localize and embed into the bacterial cell wall causing disruptions that lead to a significant reduction in bacterial viability. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=89 SRC="FIGDIR/small/616754v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@70991corg.highwire.dtl.DTLVardef@541a36org.highwire.dtl.DTLVardef@18504bcorg.highwire.dtl.DTLVardef@1fa08c3_HPS_FORMAT_FIGEXP M_FIG C_FIG