Evolution of
            <i>Mycobacterium abscessus</i>
            in the human lung: Cumulative mutations and genomic rearrangement of porin genes in patient isolates

Treatment ofMycobacterium abscessuspulmonary disease requires multiple antibiotics including intravenous β-lactams (e.g., imipenem, meropenem).M. abscessusproduces a β-lactamase (BlaMab) that inactivates β-lactam drugs but less efficiently carbapenems. Due to intrinsic and acquired resistance inM. abscessusand poor clinical outcomes, it is critical to understand the development of antibiotic resistance both within the host and in the setting of outbreaks. We compared serial longitudinally collectedM. abscessussubsp.massilienseisolates from the index case of a CF center outbreak and four outbreak-related strains. We found strikingly high imipenem resistance in the later patient isolates, including the outbreak strain (MIC >512 µg/ml). The phenomenon was recapitulated upon exposure of intracellular bacteria to imipenem. Addition of the β-lactamase inhibitor avibactam abrogated the resistant phenotype. Imipenem resistance was caused by an increase in β-lactamase activity and increasedblaMabmRNA level. Concurrent increase in transcription of precedingppiAgene indicated upregulation of the entire operon in the resistant strains. Deletion of the porinmspAcoincided with the first increase in MIC (from 8 to 32 µg/ml). A frameshift mutation inmsp2responsible for the rough colony morphology, and a SNP in ATP-dependent helicasehrpAco-occurred with the second increase in MIC (from 32 to 256 µg/ml). Increased BlaMabexpression and enzymatic activity may have been due to altered regulation of theppiA-blaMaboperon by the mutated HrpA alone, or in combination with other genes described above. This work supports using carbapenem/β-lactamase inhibitor combinations for treatingM. abscessus, particularly imipenem resistant strains.

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Evolution toward extremely high imipenem resistance in Mycobacterium abscessus outbreak strains

Le Run,

Tettelin,

Holland

et al. 2024

Antimicrob Agents Chemother

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Treatment of Mycobacterium abscessus pulmonary disease requires multiple antibiotics including intravenous β-lactams (e.g., imipenem). M. abscessus produces a β-lactamase (Bla Mab ) that inactivates β-lactam drugs but less efficiently carbapenems. Due to intrinsic and acquired resistance in M. abscessus and poor clinical outcomes, it is critical to understand the development of antibiotic resistance both within the host and in the setting of outbreaks. We compared serial longitudinally collected M. abscessus subsp. massiliense isolates from the index case of a cystic fibrosis center outbreak and four outbreak-related strains. We found strikingly high imipenem resistance in the later patient isolates, including the outbreak strain (MIC > 512 µg/mL). The phenomenon was recapitulated upon exposure of intracellular bacteria to imipenem. Addition of the β-lactamase inhibitor avibactam abrogated the resistant phenotype. Imipenem resistance was caused by an increase in β-lactamase activity and increased bla Mab mRNA level. Concurrent increase in transcription of the preceding ppiA gene indicated upregulation of the entire operon in the resistant strains. Deletion of the porin mspA coincided with the first increase in MIC (from 8 to 32 µg/mL). A frameshift mutation in msp2 responsible for the rough colony morphology and a SNP in ATP-dependent helicase hrpA cooccurred with the second increase in MIC (from 32 to 256 µg/mL). Increased Bla Mab expression and enzymatic activity may have been due to altered regulation of the ppiA-bla Mab operon by the mutated HrpA alone or in combination with other genes described above. This work supports using carbapenem/β-lactamase inhibitor combinations for treating M. abscessus , particularly imipenem-resistant strains.

show abstract

Evolution of Mycobacterium abscessus in the human lung: Cumulative mutations and genomic rearrangement of porin genes in patient isolates

Cited by 4 publications

References 54 publications

Mycobacteroides abscessus ability to interact with the host mucosal cells plays an important role in pathogenesis of the infection

Mycobacteroides abscessus ability to interact with the host mucosal cells plays an important role in pathogenesis of the infection

Evolution towards extremely high β-lactam resistance inMycobacterium abscessusoutbreak strains

Evolution toward extremely high imipenem resistance in Mycobacterium abscessus outbreak strains

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