Tobramycin enhances <i>Mycobacterium abscessus</i> fitness through <i>whiB7</i> induction.

Abstract

Nontuberculous mycobacteria (NTM) are opportunistic pathogens that cause pulmonary disease (PD) in people with bronchiectasis and other chronic airway diseases. Difficulty treating and eradicating NTM-PD highlights the need for improved understanding of bacterial mechanisms to establish chronic infections. People with the genetic disorder cystic fibrosis (CF) develop bronchiectasis and are the population at highest risk of NTM-PD, caused mainly by <i>Mycobacterium avium</i> or <i>Mycobacterium abscessus</i> (<i>Mabsc</i>). The majority of people with cystic fibrosis (pwCF) and bronchiectasis develop chronic <i>Pseudomonas aeruginosa</i> airway infections. We hypothesized that antibiotics used to treat <i>P. aeruginosa</i> infections could enhance <i>Mabsc</i> persistence in the CF airway. Here, we demonstrate that clinically relevant concentrations of tobramycin, which does not kill <i>Mabsc</i> but is frequently administered to pwCF with chronic <i>P. aeruginosa</i> infections, induced <i>Mabsc</i> expression of <i>whiB7,</i> a transcription factor that activates genes associated with resistance to host defenses. Tobramycin promoted <i>Mabsc</i> viability in the presence of hydrogen peroxide (H₂O₂), growth in human macrophages, and survival in mice. Deletion of <i>whiB7</i> reduced <i>Mabsc</i> viability in the presence of H₂O₂, decreased <i>Mabsc's</i> ability to persist in macrophages, and disrupted tobramycin's ability to enhance <i>Mabsc</i> survival. Transcriptomic data defining the tobramycin-associated WhiB7 regulon revealed differential gene expression of factors that could enhance <i>Mabsc</i> resistance to stress conditions such as those found in the CF lung. Overall, our data indicate that administration of tobramycin to pwCF may have unexpected off-target effects, enhancing <i>Mabsc whiB7</i> expression and promoting <i>Mabsc</i> persistent infection.