Kremer Laurent, de Chastellier Chantal, Dobson Gary, Gibson Kevin J C, Bifani Pablo, Balor Stéphanie, Gorvel Jean-Pierre, Locht Camille, Minnikin David E, Besra Gurdyal S
Laboratoire des Mécanismes Moléculaires de la Pathogénie Microbienne, INSERM U629, Institut Pasteur de Lille, 1, rue du Prof. Calmette, F-59019 Lille, France.
Mol Microbiol. 2005 Aug;57(4):1113-26. doi: 10.1111/j.1365-2958.2005.04717.x.
Systematic thin layer chromatographic (TLC) analysis of apolar lipids in Mycobacterium kansasii revealed the presence of a previously uncharacterized novel component. The product was ubiquitously found in a panel of M. kansasii clinical isolates, as well as other pathogenic and non-pathogenic mycobacterial species. TLC analysis of [(14)C]-acetate- or [(14)C]-glycerol-labelled M. kansasii cultures tentatively assigned the novel product as an unusual triacylglycerol-related lipid. Subsequent purification, followed by structural determination using (1)H-nuclear magnetic resonance (NMR) and electrospray mass spectrometry (ES/MS), led to the identification of this product as a monomeromycolyl-diacylglycerol (MMDAG). Treatment of M. kansasii with either isoniazid (INH), a well-known type II fatty acid synthase (FAS-II) and mycolic acid biosynthesis inhibitor, or tetrahydrolipstatin (THL), a drug approved for treating obesity, correlated with a reduced incorporation of [(14)C]-acetate into both mycolic acids and MMDAG. Addition of INH or THL to the cultures induced major morphological changes and, surprisingly, resulted in an increased number of lipid storage bodies, as determined by electron microscopy. The potent antimycobacterial activity of THL was confirmed against a variety of mycobacterial species, including INH-susceptible and -resistant Mycobacterium tuberculosis strains. Therefore, THL and other beta-lactones may be promising drugs for the development of new antitubercular therapy.
对堪萨斯分枝杆菌中非极性脂质进行的系统薄层色谱（TLC）分析揭示了一种先前未被表征的新成分的存在。该产物在一组堪萨斯分枝杆菌临床分离株以及其他致病性和非致病性分枝杆菌物种中普遍存在。对用[¹⁴C] - 乙酸盐或[¹⁴C] - 甘油标记的堪萨斯分枝杆菌培养物进行TLC分析，初步将该新产物确定为一种不寻常的与三酰甘油相关的脂质。随后进行纯化，接着使用¹H - 核磁共振（NMR）和电喷雾质谱（ES/MS）进行结构测定，从而鉴定该产物为单分枝菌酸二酰甘油（MMDAG）。用异烟肼（INH，一种著名的II型脂肪酸合酶（FAS-II）和分枝菌酸生物合成抑制剂）或四氢脂抑素（THL，一种被批准用于治疗肥胖症的药物）处理堪萨斯分枝杆菌，与[¹⁴C] - 乙酸盐掺入分枝菌酸和MMDAG的量减少相关。向培养物中添加INH或THL会引起主要的形态变化，并且令人惊讶的是，通过电子显微镜观察发现脂质储存体的数量增加。THL对多种分枝杆菌物种，包括对INH敏感和耐药的结核分枝杆菌菌株，都具有强大的抗分枝杆菌活性。因此，THL和其他β - 内酯可能是开发新型抗结核疗法的有前景的药物。
