Assessment of clofazimine and TB47 combination activity against Mycobacterium abscessus using a bioluminescent approach

Yang Liu, Yaoju Tan, M. Mahmudul Islam, Yuanyuan Cao, Xiaoyun Lu, Sheng Zeng, H. M.Adnan Hameed, Peipei Zhou, Xingshan Cai, Shuai Wang, Julius N. Mugweru, Guoliang Zhang, Huancai Yin, Jianxiong Liu, Eric Nuermberger, Tianyu Zhang

Research output: Contribution to journalArticlepeer-review

Abstract

Mycobacterium abscessus is intrinsically resistant to most antimicrobial agents. The emerging infections caused by M. abscessus and the lack of effective treatment call for rapid attention. Here, we intended to construct a selectable marker-free autoluminescent M. abscessus strain (designated UAlMab) as a real-time reporter strain to facilitate the discovery of effective drugs and regimens for treating M. abscessus. The UAlMab strain was constructed using the dif/Xer recombinase system. In vitro and in vivo activities of several drugs, including clofazimine and TB47, a recently reported cytochrome bc1 inhibitor, were assessed using UAlMab. Furthermore, the efficacy of multiple drug combinations, including the clofazimine and TB47 combination, were tested against 20 clinical M. abscessus isolates. The UAlMab strain enabled us to evaluate drug efficacy both in vitro and in live BALB/c mice in a real-time, noninvasive fashion. Importantly, although TB47 showed marginal activity either alone or in combination with clarithromycin, amikacin, or roxithromycin, the drug markedly potentiated the activity of clofazimine, both in vitro and in vivo. This study demonstrates that the use of the UAlMab strain can significantly facilitate rapid evaluation of new drugs and regimens. The clofazimine and TB47 combination is effective against M. abscessus, and dual/triple electron transport chain (ETC) targeting can be an effective therapeutic approach for treating mycobacterial infections.

Original languageEnglish (US)
Article numbere01881-19
JournalAntimicrobial agents and chemotherapy
Volume64
Issue number3
DOIs
StatePublished - 2020

Keywords

  • Autoluminescent
  • Clofazimine
  • Cytochrome bc inhibitor
  • Mycobacterium abscessus
  • TB47

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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