Schumann Nicholas C, Lee Kwang Jun, Thompson Andrew P, Salaemae Wanisa, Pederick Jordan L, Avery Thomas, Gaiser Birgit I, Hodgkinson-Bean James, Booker Grant W, Polyak Steven W, Bruning John B, Wegener Kate L, Abell Andrew D
Department of Chemistry, School of Physical Sciences, University of Adelaide, Adelaide, SA 5005, Australia.
Centre for Nanoscale BioPhotonics (CNBP), University of Adelaide, Adelaide, SA 5005, Australia.
ACS Chem Biol. 2021 Nov 19;16(11):2339-2347. doi: 10.1021/acschembio.1c00491. Epub 2021 Sep 17.
dethiobiotin synthase (DTBS) is a crucial enzyme involved in the biosynthesis of biotin in the causative agent of tuberculosis, . Here, we report a binder of DTBS, cyclopentylacetic acid ( = 3.4 ± 0.4 mM), identified screening. X-ray crystallography showed that binds in the 7,8-diaminopelargonic acid (DAPA) pocket of DTBS. Appending an acidic group to the para-position of the aromatic ring of the scaffold revealed compounds and as more potent binders, with = 19 ± 5 and 17 ± 1 μM, respectively. Further optimization identified tetrazole as a particularly potent binder ( = 57 ± 5 nM) and inhibitor ( = 5 ± 1 μM) of DTBS. Our findings highlight the first reported inhibitors of DTBS and serve as a platform for the further development of potent inhibitors and novel therapeutics for the treatment of tuberculosis.
去硫生物素合酶（DTBS）是结核病原菌生物素生物合成过程中的一种关键酶。在此，我们报告了一种通过筛选鉴定出的DTBS结合剂——环戊基乙酸（解离常数 = 3.4 ± 0.4 mM）。X射线晶体学表明，该结合剂结合在DTBS的7,8 - 二氨基壬酸（DAPA）口袋中。在支架芳香环的对位连接一个酸性基团后，发现化合物 和 是更有效的结合剂，解离常数分别为19 ± 5 μM和17 ± 1 μM。进一步优化后确定四唑 是一种特别有效的DTBS结合剂（解离常数 = 57 ± 5 nM）和抑制剂（抑制常数 = 5 ± 1 μM）。我们的研究结果突出了首次报道的DTBS抑制剂，并为进一步开发用于治疗结核病的强效抑制剂和新型疗法提供了一个平台。
