Proton Motive Force-Disrupting Antimycobacterial Guanylurea Polymer

Mycobacterial infectious diseases, including tuberculosis (TB), severely threaten global public health. Nonreplicating Mycobacterium tuberculosis (Mtb) is extremely difficult to eradicate using current TB drugs that primarily act on replicating cells. Novel TB drugs acting on unconventional targets are needed to combat TB efficiently. Although membrane-disrupting antimicrobial peptides and their synthetic mimics exhibit the potential to kill persisters, the lack of microbe selectivity, especially toward mycobacteria, has been a concern. Here, we report that the recently developed poly(guanylurea)-piperazine (PGU-P) shows fast and selective mycobactericidal effects. Using a nonpathogenic model organism, Mycobacterium smegmatis (Msm), we have found that the mycobactericidal effects of PGU-P are correlated to the disruption of the mycobacterial membrane potential and bioenergetics. Accordingly, PGU-P also potentiates bedaquiline, an oxidative phosphorylation-targeting TB drug disturbing mycobacterial bioenergetics. Importantly, PGU-P also exhibits a promising activity against pathogenic Mtb with a minimum inhibitory concentration of 37 mu g/mL. Our results support that PGU-P is a novel class of antimycobacterial biomaterial, and the unique structural feature can contribute to developing novel antimycobacterial drugs.

Automated summary

Mycobacterial infectious diseases, particularly tuberculosis (TB), are a significant global public health concern. Current TB drugs primarily target replicating cells and are ineffective against nonreplicating Mycobacterium tuberculosis (Mtb). This study reports the antimycobacterial effects of poly(guanylurea)-piperazine (PGU-P), which disrupts the mycobacterial membrane potential and bioenergetics. PGU-P also exhibits promising activity against pathogenic Mtb, making it a potential candidate for the development of novel antimycobacterial drugs.