An anti-mycobacterial conjugated oligoelectrolyte effective against <i>Mycobacterium abscessus</i>

Abstract

Infections caused by nontuberculous mycobacteria have increased more than 50% in the past two decades and more than doubled in the elderly population. <i>Mycobacterium abscessus</i> (Mab), one of the most prevalent of these rapidly growing species, is intrinsically resistant to numerous antibiotics. Current standard-of-care treatments are not satisfactory, with high failure rate and notable adverse effects. We report here a potent anti-Mab compound from the flexible molecular framework afforded by conjugated oligoelectrolytes (COEs). A screen of structurally diverse, noncytotoxic COEs identified a lead compound, COE-PNH₂, which was bactericidal against replicating, nonreplicating persisters and intracellular Mab.COE-PNH₂ had low propensity for resistance development, with a frequency of resistance below 1.25 × 10^-9 and showed no detectable resistance upon serial passaging. Mechanism of action studies were in line with COE-PNH₂ affecting the physical and functional integrity of the bacterial envelope and disrupting the mycomembrane and associated essential bioenergetic pathways. Moreover, COE-PNH₂ was well-tolerated and efficacious in a mouse model of Mab lung infection. This study highlights desirable in vitro and in vivo potency and safety index of this COE structure, which represents a promising anti-mycobacterial to tackle an unmet medical need.