Potentiating the Anti-Tuberculosis Efficacy of Peptide Nucleic Acids through Combinations with Permeabilizing Drugs

Abstract

The emergence of antimicrobial resistance warrants for the development of improved treatment approaches. In this regard, peptide nucleic acids (pnas) have shown great promise, exhibiting antibiotic properties through the targeting of cellular nucleic acids. We aimed to study the efficacy of pna as an anti-tuberculosis agent. Since the efficacy of pna is limited by its low penetration into the cell, we also investigated combinatorial treatments using permeabilizing drugs to improve pna efficacy. Various concentrations of anti-inha pna, permeabilizing drugs, and their combinations were screened against extracellular and intracellular mycobacteria.0.625 to 5 μm anti-inha pna was observed to merely inhibit the growth of extracellular m. Smegmatis, while low intracellular bacterial load was reduced by 2 or 2.5 log-fold when treated with 2.5 or 5 μm pna, respectively. Anti-inha pna against m. Tuberculosis h37ra exhibited bactericidal properties at 2.5 and 5 μm and enabled a slight reduction in intracellular m. Tuberculosis at concentrations from 2.5 to 20 μm. Of the permeabilizing drugs tested, ethambutol showed the most permeabilizing potential and ultimately potentiated anti-inha pna to the greatest extent, reducing its efficacious concentration to 1.25 μm against both m. Smegmatis and m. Tuberculosis. Furthermore, an enhanced clearance of 1.3 log-fold was observed for ethambutol-anti-inha pna combinations against intracellular m. Tuberculosis. Thus, permeabilizing drug-pna combinations indeed exhibit improved efficacies. We therefore propose that anti-inha pna could improve therapy even when applied in minute doses as an addition to the current anti-tuberculosis drug regimen. © 2022 american society for microbiology. All rights reserved.