Targeting polyketide synthase 13 for the treatment of tuberculosis

Xia, Fei; Zhang, Haoling; Yang, Huanaoyu; Zheng, Mingming; Min, Wenjian; Sun, Chengliang; Yuan, Kai; Yang, Peng

doi:10.1016/j.ejmech.2023.115702

Cited by 3 publications

(2 citation statements)

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“…Polyketide synthase 13 (Pks13: Rv3800c) was highlighted as a novel target for Mycobacterium tuberculosis growth inhibitors, as a result of the discovery of two phenotypic screening hits where resistant mutants indicated involvement of Pks13. − Pks13 is essential for mycobacterial survival − and is responsible for the last stage of mycolic acid synthesis. , These long-chain fatty acids are a characteristic of the cell wall from the genus Mycobacterium and are known to be critical for the pathogenicity, virulence, and survival of M. tuberculosis . Pks13 is a multidomain protein, containing an acyl transferase (AT) domain, a ketosynthase (KS) domain, acyl carrier protein (ACP) domains, and a thioesterase (TE) domain. , Mutants that were shown to be resistant to a benzofuran phenotypic screening hit were confirmed to contain single amino acid changes within the TE domain (D1607N and D1644G), while mutants resistant to a thiophene hit were found in the ACP domain .…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification and Optimization of Novel Inhibitors of the Polyketide Synthase 13 Thioesterase Domain with Antitubercular Activity

Green,

Wilson,

Eadsforth

et al. 2023

J. Med. Chem.

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There is an urgent need for new tuberculosis (TB) treatments, with novel modes of action, to reduce the incidence/mortality of TB and to combat resistance to current treatments. Through both chemical and genetic methodologies, polyketide synthase 13 (Pks13) has been validated as essential for mycobacterial survival and as an attractive target for Mycobacterium tuberculosis growth inhibitors. A benzofuran series of inhibitors that targeted the Pks13 thioesterase domain, failed to progress to preclinical development due to concerns over cardiotoxicity. Herein, we report the identification of a novel oxadiazole series of Pks13 inhibitors, derived from a high-throughput screening hit and structure-guided optimization. This new series binds in the Pks13 thioesterase domain, with a distinct binding mode compared to the benzofuran series. Through iterative rounds of design, assisted by structural information, lead compounds were identified with improved antitubercular potencies (MIC < 1 μM) and in vitro ADMET profiles.

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