TY - JOUR
T1 - Assessment of clofazimine and TB47 combination activity against Mycobacterium abscessus using a bioluminescent approach
AU - Liu, Yang
AU - Tan, Yaoju
AU - Islam, M. Mahmudul
AU - Cao, Yuanyuan
AU - Lu, Xiaoyun
AU - Zeng, Sheng
AU - Hameed, H. M.Adnan
AU - Zhou, Peipei
AU - Cai, Xingshan
AU - Wang, Shuai
AU - Mugweru, Julius N.
AU - Zhang, Guoliang
AU - Yin, Huancai
AU - Liu, Jianxiong
AU - Nuermberger, Eric
AU - Zhang, Tianyu
N1 - Funding Information:
This work was supported by the National Natural Science Foundation of China (81973372, 21920102003), by the National Mega-project of China for Innovative Drugs (grant number 2019ZX09721001-003-003) and for Main Infectious Diseases (2017ZX10302301-003-002), by Chinese Academy of Sciences grants (YJKYYQ20170036 and 154144KYSB20190005), Science and Technology Department of Guangdong Province (2017A020212004, GDME-2018C003, and 2019B110233003), and partially by grants (SKLRD2016ZJ003 and SKLRD-OP-201919) from the State Key Lab of Respiratory Disease, Guangzhou Institute of Respiratory Diseases, First Affiliated Hospital of Guangzhou Medical University. T.Z. received a Science and Technology Innovation Leader of Guangdong Province grant (2016TX03R095). M.M.I. received a CAS-TWAS President Fellowship for International Doctoral Students, and H.M.A.H. received a UCAS Scholarship for International Students.
Publisher Copyright:
Copyright © 2020 American Society for Microbiology. All Rights Reserved.
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - Autoluminescent
KW - Clofazimine
KW - Cytochrome bc inhibitor
KW - Mycobacterium abscessus
KW - TB47
UR - http://www.scopus.com/inward/record.url?scp=85079908295&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85079908295&partnerID=8YFLogxK
U2 - 10.1128/AAC.01881-19
DO - 10.1128/AAC.01881-19
M3 - Article
C2 - 31843996
AN - SCOPUS:85079908295
SN - 0066-4804
VL - 64
JO - Antimicrobial agents and chemotherapy
JF - Antimicrobial agents and chemotherapy
IS - 3
M1 - e01881-19
ER -