Assessment of Clofazimine and TB47 Combination Activity against Mycobacterium abscessus Using a Bioluminescent Approach

• Published in: Antimicrobial agents and chemotherapy Vol. 64; no. 3
• Main Authors: Liu, Yang, Tan, Yaoju, Islam, M Mahmudul, Cao, Yuanyuan, Lu, Xiaoyun, Zeng, Sheng, Hameed, H M Adnan, Zhou, Peipei, Cai, Xingshan, Wang, Shuai, Mugweru, Julius N, Zhang, Guoliang, Yin, Huancai, Liu, Jianxiong, Nuermberger, Eric, Zhang, Tianyu
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 21.02.2020
• Subjects: Amikacin - pharmacology; Animals; Anti-Bacterial Agents - pharmacology; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Clarithromycin - pharmacology; Clofazimine - pharmacology; Drug Combinations; Drug Resistance, Multiple, Bacterial - drug effects; Drug Resistance, Multiple, Bacterial - genetics; Drug Synergism; Electron Transport - drug effects; Electron Transport Complex III - antagonists & inhibitors; Electron Transport Complex III - genetics; Electron Transport Complex III - metabolism; Enzyme Inhibitors - pharmacology; Experimental Therapeutics; Female; Genetic Engineering - methods; Luminescence; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Mycobacterium abscessus - drug effects; Mycobacterium abscessus - genetics; Mycobacterium abscessus - metabolism; Mycobacterium Infections, Nontuberculous - drug therapy; Mycobacterium Infections, Nontuberculous - enzymology; Mycobacterium Infections, Nontuberculous - microbiology; Mycobacterium Infections, Nontuberculous - pathology; Optical Imaging - methods; Recombinases - genetics; Recombinases - metabolism; Roxithromycin - pharmacology; cytochrome bc1 inhibitor; autoluminescent; clofazimine; TB47; Mycobacterium abscessus
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.01881-19

is intrinsically resistant to most antimicrobial agents. The emerging infections caused by and the lack of effective treatment call for rapid attention. Here, we intended to construct a selectable marker-free autoluminescent strain (designated UAlMab) as a real-time reporter strain to facilitate the discovery of effective drugs and regimens for treating The UAlMab strain was constructed using the /Xer recombinase system. and activities of several drugs, including clofazimine and TB47, a recently reported cytochrome inhibitor, were assessed using UAlMab. Furthermore, the efficacy of multiple drug combinations, including the clofazimine and TB47 combination, were tested against 20 clinical isolates. The UAlMab strain enabled us to evaluate drug efficacy both 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 and 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 , and dual/triple electron transport chain (ETC) targeting can be an effective therapeutic approach for treating mycobacterial infections.