Title:Specifically Targeting Mtb Cell-Wall and TMM Transporter: The Development of MmpL3 Inhibitors
Volume: 22
Issue: 4
Author(s): Qing Luo, Huaichuan Duan, Hailian Yan, Xinyu Liu, Lianxin Peng, Yichen Hu, Wei Liu, Li Liang, Hubing Shi*, Gang Zhao*Jianping Hu *
Affiliation:
- Laboratory of Tumor Targeted and Immune Therapy, Clinical Research Center for Breast, West China Hospital, Sichuan University, Chengdu 610065,China
- Key Laboratory of Coarse Cereal Processing, Ministry of Agriculture and Rural Affairs, School of Pharmacy, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu 610106,China
- Key Laboratory of Coarse Cereal Processing, Ministry of Agriculture and Rural Affairs, School of Pharmacy, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu 610106,China
Keywords:
Anti-tubercular agents, M. tuberculosis, MmpL3, inhibitor, structure-activity relationship, TMM transporter.
Abstract: Tuberculosis (TB) remains a serious threat to whole human health. In particular, the drug
resistance of Mycobacterium tuberculosis (Mtb) has become a huge challenge in clinical medicine,
and it is extremely urgent to develop effective inhibitors with novel structures and mechanisms. Belonging
to the Resistance, Nodulation and Division (RND) superfamily, Mycobacterial membrane
proteins Large 3 (MmpL3) is mainly responsible for transporting mycolic acid outside cell membrane
to form cell wall, and plays critical roles in iron acquisition which is vital to the survival of
Mtb. As a potential Mtb target in recent years, its inhibitor research has attracted wide attention. A
series of inhibitors (such as SQ109, AU1235, BM212, etc.) through experimental screening have
been reported in succession, especially SQ109 has entered the clinical stage. In this paper, the structural
biology information of target MmpL3 was summarized, and the structure-activity relationship
(SAR) of inhibitors reported in recent years and their inhibitory mechanism both were reviewed,
aiming to provide help for the rational design of MmpL3 inhibitors in the future.
