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Late-Stage Functionalization of Platensimycin Leading to Multiple Analogues with Improved Antibacterial Activity in Vitro and in Vivo.


ABSTRACT: Bacterial fatty acid synthases are promising antibacterial targets against multidrug-resistant pathogens. Platensimycin (PTM) is a potent FabB/FabF inhibitor, while its poor pharmacokinetics hampers the clinical development. In this study, a focused library of PTM derivatives was prepared through thiolysis of PTM oxirane (1), followed by various C-C cross-coupling reactions in high yields. Antibacterial screening of these compounds in vitro yielded multiple hits with improved anti-Staphylococcus activities over PTM. Among them, compounds A1, A3, A17, and A28 exhibited improved antibacterial activities over PTM against methicillin-resistant Staphylococcus aureus (MRSA) in a mouse peritonitis model. Compound A28 was further shown to be effective against MRSA infection in a mouse wound model, in comparison to mupirocin. Therefore, the facile preparation and screening of these PTM derivatives, together with their potent antibacterial activities in vivo, suggest a promising strategy to improve the antibacterial activity and pharmacokinetic properties of PTM.

SUBMITTER: Deng Y 

PROVIDER: S-EPMC6755679 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Late-Stage Functionalization of Platensimycin Leading to Multiple Analogues with Improved Antibacterial Activity in Vitro and in Vivo.

Deng Youchao Y   Weng Xiang X   Li Yuling Y   Su Meng M   Wen Zhongqing Z   Ji Xinxin X   Ren Nan N   Shen Ben B   Duan Yanwen Y   Huang Yong Y  

Journal of medicinal chemistry 20190702 14


Bacterial fatty acid synthases are promising antibacterial targets against multidrug-resistant pathogens. Platensimycin (PTM) is a potent FabB/FabF inhibitor, while its poor pharmacokinetics hampers the clinical development. In this study, a focused library of PTM derivatives was prepared through thiolysis of PTM oxirane (<b>1</b>), followed by various C-C cross-coupling reactions in high yields. Antibacterial screening of these compounds in vitro yielded multiple hits with improved anti-<i>Stap  ...[more]

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