Open AccessSemisynthesis and Biological Evaluation of Platencin Thioether Derivatives: Dual FabF and FabH Inhibitors against MRSA
Author(s) -
Yuling Li,
Xiang Weng,
Youchao Deng,
Jian Pan,
Saibin Zhu,
Zhongqing Wen,
Yanqiu Yuan,
Shaowen Li,
Ben Shen,
Yanwen Duan,
Yong Huang
Publication year - 2021
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.0c00653
Subject(s) - semisynthesis , antibacterial activity , chemistry , antibiotics , biochemistry , isothermal titration calorimetry , staphylococcus aureus , in vivo , microbiology and biotechnology , bacteria , biology , genetics
The discovery and clinical use of multitarget monotherapeutic antibiotics is regarded as a promising approach to reduce the development of antibiotic resistance. Platencin (PTN), a potent natural antibiotic initially isolated from a soil actinomycete, targets both FabH and FabF, the initiation and elongation condensing enzymes for bacterial fatty acid biosynthesis. However, its further clinical development has been hampered by poor pharmacokinetics. Herein we report the semisynthesis and biological evaluation of platencin derivatives 1 - 15 with potent antibacterial activity against methicillin-resistant Staphylococcus aureus in vitro. Some of these PTN analogues showed similar yet distinct interactions with FabH and FabF, as shown by molecular docking, differential scanning fluorometry, and isothermal titration calorimetry. Compounds 3 , 8 , 10 , and 14 were further evaluated in a mouse peritonitis model, among which 8 showed in vivo antibacterial activity comparable to that of PTN. Our results suggest that semisynthetic modification of PTN is a rapid route to obtain active PTN derivatives that might be further developed as promising antibiotics against drug-resistant major pathogens.