Jain Madhulika, Petzold Christopher J, Schelle Michael W, Leavell Michael D, Mougous Joseph D, Bertozzi Carolyn R, Leary Julie A, Cox Jeffery S
Department of Microbiology and Immunology, Program in Microbial Pathogenesis and Host Defense, University of California, San Francisco, CA 94143, USA.
Proc Natl Acad Sci U S A. 2007 Mar 20;104(12):5133-8. doi: 10.1073/pnas.0610634104. Epub 2007 Mar 8.
Mycobacterium tuberculosis synthesizes specific polyketide lipids that interact with the host and are required for virulence. Using a mass spectrometric approach to simultaneously monitor hundreds of lipids, we discovered that the size and abundance of two lipid virulence factors, phthiocerol dimycocerosate (PDIM) and sulfolipid-1 (SL-1), are controlled by the availability of a common precursor, methyl malonyl CoA (MMCoA). Consistent with this view, increased levels of MMCoA led to increased abundance and mass of both PDIM and SL-1. Furthermore, perturbation of MMCoA metabolism attenuated pathogen replication in mice. Importantly, we detected increased PDIM synthesis in bacteria growing within host tissues and in bacteria grown in culture on odd-chain fatty acids. Because M. tuberculosis catabolizes host lipids to grow during infection, we propose that growth of M. tuberculosis on fatty acids in vivo leads to increased flux of MMCoA through lipid biosynthetic pathways, resulting in increased virulence lipid synthesis. Our results suggest that the shift to host lipid catabolism during infection allows for increased virulence lipid anabolism by the bacterium.
结核分枝杆菌合成特定的聚酮类脂质，这些脂质与宿主相互作用且是毒力所必需的。我们采用质谱方法同时监测数百种脂质，发现两种脂质毒力因子，即结核硬脂酸二霉菌酸酯（PDIM）和硫脂-1（SL-1）的大小和丰度受共同前体甲基丙二酰辅酶A（MMCoA）可用性的控制。与此观点一致，MMCoA水平升高导致PDIM和SL-1的丰度和质量增加。此外，MMCoA代谢的扰动减弱了病原体在小鼠体内的复制。重要的是，我们在宿主组织内生长的细菌以及在奇数链脂肪酸培养基中生长的细菌中检测到PDIM合成增加。由于结核分枝杆菌在感染期间分解宿主脂质以生长，我们提出结核分枝杆菌在体内脂肪酸上的生长导致MMCoA通过脂质生物合成途径的通量增加，从而导致毒力脂质合成增加。我们的结果表明，感染期间向宿主脂质分解代谢的转变使得细菌能够增加毒力脂质的合成代谢。
