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<p>Nontuberculous mycobacteria (NTM) cause difficult-to-treat pulmonary infections due to their high antimicrobial resistance. Among them, the <i>Mycobacterium abscessus</i> complex (MABC) is a major pathogen characterized by prolonged treatment courses and low success rates. This study investigated the combination effects of the antimicrobials bedaquiline (BDQ) and clarithromycin (CLA) with the efflux pump inhibitors (EPIs) verapamil (VP) and berberine (BER) in clinical MABC isolates. Nineteen MABC strains isolated from respiratory samples were analyzed using the checkerboard method, and fractional inhibitory concentration index (FICI) values were calculated to determine synergistic, indifferent, or antagonistic interactions. Subspecies identification and genotypic resistance profiles were assessed using the GenoType NTM-DR assay. Of the isolates, 84.2% were identified as <i>M. abscessus</i> subsp. <i>abscessus</i>, 10.5% as <i>M. abscessus</i> subsp. <i>massiliense</i>, and 5.26% as <i>M. abscessus</i> subsp. <i>bolletii</i>. While no <i>rrl</i> (acquired macrolide resistance) or <i>rrs</i> (aminoglycoside resistance) mutations were detected, a functional <i>erm41</i> (inducible macrolide resistance) gene was found in 73.6% of isolates. Synergistic effects were observed at rates of 84.2% for BDQ/VP, 57.9% for CLA/VP, 5.26% for BDQ/BER, and 31.5% for CLA/BER, with no antagonism identified. The BDQ/VP combination showed significantly greater synergy than BDQ/BER (<i>p</i> &lt; <i>0.0005</i>) and was superior to CLA/VP (<i>p</i> &lt; <i>0.0005</i>). Combinations with VP demonstrated significantly lower FICI values (<i>p</i> &lt; <i>0.0005).</i> Median fold increases in antimicrobial activity were four-fold with VP and two-fold with BER. In conclusion, the BDQ/VP combination emerged as the most effective regimen. These results highlight the synergistic potential of EPI-antimicrobial combinations and may inform the development of new therapeutic strategies for NTM infections.</p>

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Evaluation of the interaction and synergy potential of bedaquiline and clarithromycin in combination with efflux pump inhibitors in clinical isolates of Mycobacterium abscessus complex

  • 期刊论文

  • 发表日期：

    2025年10月11日

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  • Esra Gül Tursun,
  • Taylan Bozok,
  • Can Biçmen,
  • Gönül Aslan

摘要

Nontuberculous mycobacteria (NTM) cause difficult-to-treat pulmonary infections due to their high antimicrobial resistance. Among them, the Mycobacterium abscessus complex (MABC) is a major pathogen characterized by prolonged treatment courses and low success rates. This study investigated the combination effects of the antimicrobials bedaquiline (BDQ) and clarithromycin (CLA) with the efflux pump inhibitors (EPIs) verapamil (VP) and berberine (BER) in clinical MABC isolates. Nineteen MABC strains isolated from respiratory samples were analyzed using the checkerboard method, and fractional inhibitory concentration index (FICI) values were calculated to determine synergistic, indifferent, or antagonistic interactions. Subspecies identification and genotypic resistance profiles were assessed using the GenoType NTM-DR assay. Of the isolates, 84.2% were identified as M. abscessus subsp. abscessus, 10.5% as M. abscessus subsp. massiliense, and 5.26% as M. abscessus subsp. bolletii. While no rrl (acquired macrolide resistance) or rrs (aminoglycoside resistance) mutations were detected, a functional erm41 (inducible macrolide resistance) gene was found in 73.6% of isolates. Synergistic effects were observed at rates of 84.2% for BDQ/VP, 57.9% for CLA/VP, 5.26% for BDQ/BER, and 31.5% for CLA/BER, with no antagonism identified. The BDQ/VP combination showed significantly greater synergy than BDQ/BER (p < 0.0005) and was superior to CLA/VP (p < 0.0005). Combinations with VP demonstrated significantly lower FICI values (p < 0.0005). Median fold increases in antimicrobial activity were four-fold with VP and two-fold with BER. In conclusion, the BDQ/VP combination emerged as the most effective regimen. These results highlight the synergistic potential of EPI-antimicrobial combinations and may inform the development of new therapeutic strategies for NTM infections.