Investigation of (S)-(-)-Acidomycin: A Selective Antimycobacterial Natural Product That Inhibits Biotin Synthase
Investigation of (S)-(-)-Acidomycin: A Selective Antimycobacterial Natural Product That Inhibits Biotin Synthase
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DOI：
10.1021/acsinfecdis.8b00345
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发表时间：
2019-04-01
影响因子：
5.3
通讯作者：
Aldrich, Courtney C.
中科院分区：
文献类型：
--
作者：
Bockman, Matthew R.;Engelhart, Curtis A.;Aldrich, Courtney C.
本文介绍了(S)-(-)-酸霉素的合成、绝对立体构型、完整生物学特性、作用机制、耐药机制和药动学性质。酸霉素对一系列当代药敏和耐药结核分枝杆菌菌株具有良好的抗结核活性（最低抑制浓度(mic) = 0.096-6.2 μ M），但对非结核分枝杆菌和革兰氏阳性和革兰氏阴性病原体（mic bb0 - 1000 μ M）无活性。与生物素合成途径中间体的互补研究和随后的生化研究证实，酸霉素通过竞争性抑制生物素合成酶（BioB）抑制生物素合成，K-i约为1 μ M，并刺激s -腺苷- l-甲硫氨酸（SAM）的非生产裂解，产生有毒的代谢物5'-脱氧腺苷。细胞研究表明，酸霉素选择性地在结核分枝杆菌中积累，为观察到的抗菌活性提供了机制基础。结核分枝杆菌对酸霉素自发耐药的发展是困难的，通过过表达BioB只观察到对酸霉素的低水平耐药。总的来说，这些结果为进一步推进酸霉素的研究奠定了基础，并突出了BioB作为一个有前景的靶点。
The synthesis, absolute stereochemical configuration, complete biological characterization, mechanism of action and resistance, and pharmacokinetic properties of (S)-(-)-acidomycin are described. Acidomycin possesses promising antitubercular activity against a series of contemporary drug susceptible and drug-resistant M. tuberculosis strains (minimum inhibitory concentrations (MICs) = 0.096-6.2 mu M) but is inactive against nontuberculosis mycobacteria and Gram-positive and Gram-negative pathogens (MICs > 1000 mu M). Complementation studies with biotin biosynthetic pathway intermediates and subsequent biochemical studies confirmed acidomycin inhibits biotin synthesis with a K-i of approximately 1 mu M through the competitive inhibition of biotin synthase (BioB) and also stimulates unproductive cleavage of S-adenosyl-L-methionine (SAM) to generate the toxic metabolite 5'-deoxyadenosine. Cell studies demonstrate acidomycin selectively accumulates in M. tuberculosis providing a mechanistic basis for the observed antibacterial activity. The development of spontaneous resistance by M. tuberculosis to acidomycin was difficult, and only low-level resistance to acidomycin was observed by overexpression of BioB. Collectively, the results provide a foundation to advance acidomycin and highlight BioB as a promising target.