Semisynthesis and Biological Evaluation of Platencin Thioether Derivatives: Dual FabF and FabH Inhibitors against MRSA

Yuling Li; Xiang Weng; Youchao Deng; Jian Pan; Saibin Zhu; Zhongqing Wen; Yanqiu Yuan; Shaowen Li; Ben Shen; Yanwen Duan; Yong Huang

doi:10.1021/acsmedchemlett.0c00653

Semisynthesis and Biological Evaluation of Platencin Thioether Derivatives: Dual FabF and FabH Inhibitors against MRSA

ACS Med Chem Lett. 2021 Feb 15;12(3):433-442. doi: 10.1021/acsmedchemlett.0c00653. eCollection 2021 Mar 11.

Authors

Yuling Li¹, Xiang Weng¹, Youchao Deng¹, Jian Pan¹, Saibin Zhu¹, Zhongqing Wen¹, Yanqiu Yuan², Shaowen Li³, Ben Shen⁴, Yanwen Duan^{1

5

6}, Yong Huang^{1

6}

Affiliations

¹ Xiangya International Academy of Translational Medicine at Central South University, Changsha, Hunan 410013, China.
² School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
³ State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei 430070, China.
⁴ Departments of Chemistry and Molecular Medicine and Natural Product Discovery Center at Scripps Research, Scripps Research, Jupiter, Florida 33458, United States.
⁵ Hunan Engineering Research Center of Combinatorial Biosynthesis and Natural Product Drug Discovery, Changsha, Hunan 410011, China.
⁶ National Engineering Research Center of Combinatorial Biosynthesis for Drug Discovery, Changsha, Hunan 410011, China.

Abstract

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.