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Tobramycin enhances Mycobacterium abscessus fitness through whiB7 induction

ABSTRACT: Nontuberculous mycobacteria (NTM) are opportunistic pathogens that cause pulmonary disease (PD) in people with bronchiectasis and other chronic airways 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 Mycobacterium avium or Mycobacterium abscessus (Mabsc). The majority of people with CF (pwCF) and bronchiectasis develop chronic Pseudomonas aeruginosa airway infections. We hypothesized that antibiotics used to treat P. aeruginosa infections could enhance Mabsc persistence in the CF airway. Here we demonstrate that clinically relevant concentrations of tobramycin, which does not kill Mabsc but is frequently administered to pwCF with chronic P. aeruginosa infections, induced Mabsc expression of whiB7, a transcription factor that activates genes associated with resistance to host defenses. Tobramycin promoted Mabsc viability in the presence of (H2O2), growth in human macrophages, and survival in mice. Deletion of whiB7 reduced Mabsc viability in the presence of H2O2, decreased Mabsc’s ability to persist in macrophages, and disrupted tobramycin’s ability to enhance Mabsc survival. Transcriptomic data defining the tobramycin associated WhiB7 regulon revealed differential gene expression of factors that could enhance Mabsc resistance to stress conditions such as those in found in the CF lung. Overall, our data indicate that administration of tobramycin to pwCF may have unexpected off-target effects, enhancing Mabsc whiB7 expression and promoting Mabsc persistent infection.

ORGANISM(S): Mycobacteroides abscessus

PROVIDER: GSE344714 | GEO | 2026/09/17

REPOSITORIES: GEO

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Project description:Chronic infections with Pseudomonas aeruginosa are a leading cause of morbidity and mortality in persons with cystic fibrosis (pwCF). P. aeruginosa persists in the CF lung by utilizing adaptation strategies to cause infection, including altering the expression of metabolic genes to acquire nutrients that are abundant in the CF airway. Glycerol in the airway is imported and metabolized by the glp regulon, which is under the control of the GlpR repressor. It has been shown that the loss of GlpR results in increased biofilm development in P. aeruginosa CF isolate compared to a wound isolate. Based on the increased biofilm phenotype observed and because biofilms are associated with increased antibiotic tolerance, we questioned whether GlpR plays a role in mediating antibiotic resistance of P. aeruginosa. We measured tobramycin tolerance in wild-type and glpR-defective P. aeruginosa isolates from the CF airway (FRD1) and a wound (PAO1). Cultures were grown in lysogeny broth or synthetic cystic fibrosis sputum consisting of the base formula of primarily amino acids (SCFM1) or supplemented with mucins and DNA (SCFM2), with dose-dependent concentrations of tobramycin. We tested the impact of a glpR mutation on P. aeruginosa adherence on bronchial epithelial cells from pwCF (CFBE) in the presence of tobramycin. CFBE cells were inoculated at an MOI of ~1:20 for 1 hour, given fresh apical media for 5 more hours, then apical and basal media was replaced with media containing 20 µg/ml tobramycin. We measured colony forming units (CFUs) and lactate dehydrogenase (LDH) release for cytotoxicity. Loss of glpR increased tolerance to tobramycin in both the PAO1 and FRD1 backgrounds in vitro at a concentration of 0.625 µg/mL in lysogeny broth and SCFM1. On both CFBE’s and 16HBE’s, the antibiotic resistance phenotype was more prominent in FRD1 glpR with a 2-log increase in viable bacteria when grown on cells and treated with 20 ug/ml tobramycin. However, changes in cytotoxicity where not observed between wildtype and GlpR mutants as LDH measurements were not significantly different. Our results indicate that GlpR may regulate antibiotic tolerance, in addition to biofilm development and glycerol metabolism. Additional studies are necessary to determine the mechanism of how GlpR modulates biofilm development and antibiotic tolerance.

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Tobramycin enhances Mycobacterium abscessus fitness through whiB7 induction

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