Microbial pathogenesis · 2026
Activity of OPC-167832 Against Mycobacterium abscessus and Mycobacterium chelonae: In Vitro, Intracellular, and In Vivo Assessment Using a Zebrafish Infection Model.
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Chen Siyi, Zhang Chao, Geng Zhi, Qi Zhenyan, Li Junjie, Gu Yuzhen, Ji Yuanfei, Wu Jing, Yan Bo, Yu Xia, Huang Hairong
Аннотация
OBJECTIVE: The intrinsic drug resistance of Mycobacterium abscessus (M. abscessus) makes infections caused by this pathogen difficult to treat. This study aimed to evaluate OPC-167832 as a potential drug candidate against M. abscessus.
METHODS: The in vitro activities of OPC-167832 against M. abscessus and Mycobacterium chelonae (M. chelonae) were evaluated. DprE1-mediated resistance to OPC-167832 was investigated by mutation analysis, molecular docking, molecular dynamics simulations and overexpression of DprE1 in M. abscessus. The intracellular and in vivo efficacy was further evaluated in M. abscessus subsp. abscessus (Mab) ATCC 19977, the latter using a zebrafish infection model.
RESULTS: Among 51 M. abscessus and 15 M. chelonae clinical isolates, the MIC50/MIC90 values of OPC-167832 were 0.125/0.5 μg/mL and 4/8 μg/mL, respectively. Specifically, OPC-167832 was bacteriostatic against Mab ATCC 19977 but bactericidal against M. chelonae clinical isolate 2394. Mechanistically, molecular dynamics simulations suggested that five of six DprE1 substitutions (Val72Leu, Val74Ile , Gly222Ser, Leu321Phe, Val135Ile) identified in clinical M. abscessus isolates with elevated MICs may alter OPC-167832-DprE1 interactions, even though molecular docking predicted that these substitutions exhibited docking scores similar to the wild-type complex at approximately -10.4 kcal/mol. In support of this target-related resistance mechanism, DprE1 overexpression led to a four-fold increase in the OPC-167832 MIC in M. abscessus. Furthermore, OPC-167832 inhibited the intracellular growth of the Mab reference strain in a concentration- and time-dependent manner. At 72 h, OPC-167832 at 4 μg/mL reduced the bacterial burden by approximately 1.9 log10 CFU. Consistently, in a zebrafish Mab infection model, OPC-167832 showed concentration-dependent efficacy, reducing bacterial burden by 0.48-log10 CFU and fluorescence intensity by 83.8% at 1 μg/mL.
CONCLUSIONS: OPC-167832 could be considered a promising drug candidate for the treatment of M. abscessus and M. chelonae. DprE1 is a relevant target of OPC-167832 in M. abscessus, warranting further investigation of target-associated resistance and combinatorial regimens.
METHODS: The in vitro activities of OPC-167832 against M. abscessus and Mycobacterium chelonae (M. chelonae) were evaluated. DprE1-mediated resistance to OPC-167832 was investigated by mutation analysis, molecular docking, molecular dynamics simulations and overexpression of DprE1 in M. abscessus. The intracellular and in vivo efficacy was further evaluated in M. abscessus subsp. abscessus (Mab) ATCC 19977, the latter using a zebrafish infection model.
RESULTS: Among 51 M. abscessus and 15 M. chelonae clinical isolates, the MIC50/MIC90 values of OPC-167832 were 0.125/0.5 μg/mL and 4/8 μg/mL, respectively. Specifically, OPC-167832 was bacteriostatic against Mab ATCC 19977 but bactericidal against M. chelonae clinical isolate 2394. Mechanistically, molecular dynamics simulations suggested that five of six DprE1 substitutions (Val72Leu, Val74Ile , Gly222Ser, Leu321Phe, Val135Ile) identified in clinical M. abscessus isolates with elevated MICs may alter OPC-167832-DprE1 interactions, even though molecular docking predicted that these substitutions exhibited docking scores similar to the wild-type complex at approximately -10.4 kcal/mol. In support of this target-related resistance mechanism, DprE1 overexpression led to a four-fold increase in the OPC-167832 MIC in M. abscessus. Furthermore, OPC-167832 inhibited the intracellular growth of the Mab reference strain in a concentration- and time-dependent manner. At 72 h, OPC-167832 at 4 μg/mL reduced the bacterial burden by approximately 1.9 log10 CFU. Consistently, in a zebrafish Mab infection model, OPC-167832 showed concentration-dependent efficacy, reducing bacterial burden by 0.48-log10 CFU and fluorescence intensity by 83.8% at 1 μg/mL.
CONCLUSIONS: OPC-167832 could be considered a promising drug candidate for the treatment of M. abscessus and M. chelonae. DprE1 is a relevant target of OPC-167832 in M. abscessus, warranting further investigation of target-associated resistance and combinatorial regimens.