Proton Motive Force-Disrupting Antimycobacterial Guanylurea Polymer

Abstract

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 μg/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.

Progress in Treatment and Diagnostics of Infectious Disease with Polymers

“…48 Recently developed poly(guanylurea)-pierazine was tested against Mycobecterium smegmatis (Msm) and showed a MIC of 37 μg/mL against M.tb. 49 Cationic polymers with nucleic acids (polyplexes) also play an important role in treating TB. Similarly, cationic chitosan oligosaccharide NPs were encapsulated with siRNA (by electrostatic interactions) with the help of the cross-linking agent, e.g., pentasodium-tripolyphosphate and used to deliver the same in cells against Bfl-1/A1 from the Bcl-2 protein family.…”

“…These formulations also showed enhanced killing efficiency when clofazimine was also encapsulated in polymer capsules . Recently developed poly­(guanylurea)-pierazine was tested against Mycobecterium smegmatis (Msm) and showed a MIC of 37 μg/mL against M.tb …”