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Evolution Toward Extremely High Imipenem Resistance in Mycobacterium Abscessus Outbreak Strains.

bioRxiv the preprint server for biology(2024)

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Abstract
Treatment of Mycobacterium abscessus pulmonary disease requires multiple antibiotics including intravenous beta-lactams (e.g., imipenem). M. abscessus produces a beta-lactamase (BlaMab) that inactivates beta-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 mu g/mL). The phenomenon was recapitulated upon exposure of intracellular bacteria to imipenem. Addition of the beta-lactamase inhibitor avibactam abrogated the resistant phenotype. Imipenem resistance was caused by an increase in beta-lactamase activity and increased blaMab 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 mu g/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 mu g/mL). Increased BlaMab expression and enzymatic activity may have been due to altered regulation of the ppiA-blaMab operon by the mutated HrpA alone or in combination with other genes described above. This work supports using carbapenem/beta-lactamase inhibitor combinations for treating M. abscessus, particularly imipenem-resistant strains.
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Key words
NTM,beta-lactam,antimicrobial resistance
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