Inhibitors of acetohydroxyacid synthase as promising agents against non-tuberculous mycobacterial diseases.

IF 2.1 4区医学 Q3 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Journal of Antibiotics Pub Date : 2024-12-13 DOI:10.1038/s41429-024-00799-z

Tam Doan Nguyen, Ji-Ae Choi, Hee-Jong Lim, Chong Hak Chae, Junghwan Lee, Sang-Hun Son, Jaewhan Kim, Doyi Son, Hwa-Jung Kim, Chang-Hwa Song

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引用次数: 0

Abstract

Acetohydroxyacid synthase (AHAS), exclusively present in microorganisms and plants, is a promising target for several herbicides due to its catalytic role in the branched-chain amino acid biosynthetic pathway. Previous studies have shown that K13787, a pyrazolopyrimidine sulfonamide AHAS inhibitor, was moderately effective against pulmonary infection caused by M. tuberculosis and nontuberculous mycobacteria (NTM). In this study, we synthesized various structural derivatives of K13787 based on the molecular docking studies and assessed their MICs against mycobacteria species. Among the synthetic compounds screened, K13787, along with KNT2077 and KNT2099, exhibited inhibitory efficacy against M. avium and M. abscessus, including CLR-resistant NTM species. Notably, these compounds displayed a synergistic effect (FIC ≤ 0.5) when combined with CLR against M. avium and M. abscessus. Our findings suggest that these newly identified AHAS-targeted compounds hold promise as lead candidates for novel antimycobacterial agents against NTM infections. Considering the structure-activity relationship, K13787, KNT2077, and KTN2099 emerge as potential treatments for NTM species.

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乙酰羟基酸合酶抑制剂作为抗非结核分枝杆菌疾病的有前途的药物。

乙酰羟基酸合成酶（AHAS）只存在于微生物和植物中，由于其在支链氨基酸生物合成途径中的催化作用，它是几种除草剂的有望靶点。先前的研究表明，吡唑嘧啶磺酰胺 AHAS 抑制剂 K13787 对结核杆菌和非结核分枝杆菌（NTM）引起的肺部感染有一定疗效。在本研究中，我们根据分子对接研究合成了 K13787 的多种结构衍生物，并评估了它们对分枝杆菌的 MICs。在筛选出的合成化合物中，K13787、KNT2077 和 KNT2099 对阿维菌素和脓肿霉菌（包括耐 CLR 的 NTM 菌种）具有抑制作用。值得注意的是，当这些化合物与 CLR 联用时，对阿维菌和脓肿霉具有协同作用（FIC ≤ 0.5）。我们的研究结果表明，这些新发现的 AHAS 靶向化合物有望成为新型抗 NTM 感染的候选抗霉菌药物。考虑到结构-活性关系，K13787、KNT2077 和 KTN2099 有可能成为治疗 NTM 物种的药物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Antibiotics 医学-免疫学

CiteScore

6.60

自引率

3.00%

发文量

审稿时长

1 months

期刊介绍： The Journal of Antibiotics seeks to promote research on antibiotics and related types of biologically active substances and publishes Articles, Review Articles, Brief Communication, Correspondence and other specially commissioned reports. The Journal of Antibiotics accepts papers on biochemical, chemical, microbiological and pharmacological studies. However, studies regarding human therapy do not fall under the journal’s scope. Contributions regarding recently discovered antibiotics and biologically active microbial products are particularly encouraged. Topics of particular interest within the journal''s scope include, but are not limited to, those listed below: Discovery of new antibiotics and related types of biologically active substances Production, isolation, characterization, structural elucidation, chemical synthesis and derivatization, biological activities, mechanisms of action, and structure-activity relationships of antibiotics and related types of biologically active substances Biosynthesis, bioconversion, taxonomy and genetic studies on producing microorganisms, as well as improvement of production of antibiotics and related types of biologically active substances Novel physical, chemical, biochemical, microbiological or pharmacological methods for detection, assay, determination, structural elucidation and evaluation of antibiotics and related types of biologically active substances Newly found properties, mechanisms of action and resistance-development of antibiotics and related types of biologically active substances.