MarR-Dependent Transcriptional Regulation of
            <i>mmpSL5</i>
            Induces Ethionamide Resistance in Mycobacterium abscessus

Mycobacterium abscessusis a pulmonary pathogen that exhibits intrinsic resistance to antibiotics, but the factors driving this resistance are incompletely understood. Insufficient intracellular drug accumulation could explain broad-spectrum resistance, but whether antibiotics fail to accumulate inM. abscessusand the mechanisms required for drug exclusion remain poorly understood. We measured antibiotic accumulation inM. abscessususing mass spectrometry and found a wide range of drug accumulation across clinically relevant antibiotics. Of these compounds, linezolid accumulates the least, suggesting that inadequate uptake impacts its efficacy. We utilized transposon mutagenesis screening to identify genes that cause linezolid resistance and found multiple transporters that promote membrane permeability or efflux, including an uncharacterized,M. abscessus-specific protein that effluxes linezolid and several chemically related antibiotics. This demonstrates that membrane permeability and drug efflux are critical mechanisms of antibiotic resistance inM. abscessusand suggests that targeting membrane transporters could potentiate the efficacy of certain antibiotics.

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The gene MAB_2362 is responsible for intrinsic resistance to various drugs and virulence in Mycobacterium abscessus by regulating cell division

Ju,

Li,

Zhang

et al. 2024

Antimicrob Agents Chemother

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Mycobacterium abscessus exhibits intrinsic resistance to most antibiotics, hence leading to infections that are difficult to treat. To address this issue, the identification of new molecular targets is essential for the development or repositioning of therapeutic agents. This study demonstrated that the MAB_2362 -knockout strain, Mab Δ2362 , became significantly susceptible to a range of antibiotics, not only in vitro but also exhibited susceptibility to rifabutin, bedaquiline, and linezolid in vivo . While the bacterial burden of the wild-type M. abscessus (Mab Wt ) increased by over 1 log 10 CFU/lung in a murine infection model 16 days post-infection, that of Mab Δ2362 strain decreased by more than 1 log 10 CFU/lung, which suggests that the disruption leads to attenuation. Bioinformatics analysis revealed that MAB_2362 shares the highest similarity (41.35%) with SteA, a protein known to influence cell division in Corynebacterium glutamicum , suggesting that MAB_2362 might be involved in cell division. Mab Δ2362 cells exhibited a median length of 2.62 µm, which was substantially longer than the 1.44 µm recorded for Mab Wt cells. Additionally, multiple cell division septa were observed in 42% of Mab Δ2362 cells, whereas none were seen in Mab Wt cells. An ethidium bromide uptake assay further suggested a higher cell envelope permeability in Mab Δ2362 compared to Mab Wt . Collectively, these findings underscore the role of MAB_2362 in intrinsic resistance and virulence of M. abscessus possibly through the regulation of cell division. Thus, MAB_2362 emerges as a promising candidate for targeted interventions in the pursuit of novel antimicrobials against M. abscessus .

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MarR-Dependent Transcriptional Regulation of mmpSL5 Induces Ethionamide Resistance in Mycobacterium abscessus

Cited by 4 publications

References 71 publications

TetR family transcriptional regulators: Lipid metabolism and drug resistance in mycobacteria

TetR family transcriptional regulators: Lipid metabolism and drug resistance in mycobacteria

Efflux pumps and membrane permeability contribute to intrinsic antibiotic resistance inMycobacterium abscessus

The gene MAB_2362 is responsible for intrinsic resistance to various drugs and virulence in Mycobacterium abscessus by regulating cell division

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