Structural and functional studies of mycolic acid synthesis in Mycobacterium tuberculosis

尽管发达国家通过抗生素控制了结核病，但它仍然是一个全球比例的公共卫生问题。新出现的结核杆菌(结核分枝杆菌)菌株已经对当今的一种或几种抗结核药物产生了抗药性，这让问题变得更加严重。迫切需要新的和更有效的治疗方案来控制结核病。自科赫时代以来，结核分枝杆菌和相关生物一直以包裹细菌的厚厚的蜡状包膜而闻名。这种细胞膜由高度组织化的层状结构中的脂类、多糖和多肽组成。我们部分地了解这些组件是如何由芽孢杆菌制造和组装的，但在许多方面的理解是不完整的。这项建议关注的是细胞包膜中一种名为真菌酸的成分，它占结核杆菌生物量的10%，是生存所必需的。真菌酸是一种特殊的脂肪酸，由一条特有的长臂和一条较短的臂组成，前者是分枝菌甲酸链，后者是α-烷基链。我们有兴趣澄清几种酶的三维原子结构，这些酶构成了生产真菌酸的催化装配线的一部分。我们也有兴趣了解这些酶如何与装配线上的其他组件一起工作，以及这是如何受到调节的。我们使用X射线结晶学和一系列其他实验技术，为我们提供有关酶的分子结构的细节，以及它们之间发生的相互作用。这些信息将提供对霉菌酸合成的更完整的了解，从长远来看，可能有助于寻找针对这种古老的人类对手的新疗法。

Despite the containment of tuberculosis (TB) in the developed world through antibiotics, it remains a public health problem of global proportion. The problem is made worse by emerging strains of the tubercle bacillus (Mycobacterium tuberculosis) that have become resistant against one or several of today's antitubercular drugs. New and more effective treatment options are urgently needed to control TB. Since the time of Koch, M. tuberculosis and related organisms have been known for the thick, waxy envelope surrounding the bacterium. This cell envelope comprises lipid, polysaccharide and peptide components in a highly organised layered structure. We understand in part, how these components are made and assembled by the bacillus, but the understanding is incomplete in many respects. This proposal focuses on a component of the cell envelope called mycolic acids, which make up to 10% of the biomass of the tubercle bacillus and are essential for survival. Mycolic acids are a particular kind of fatty acids that comprise a characteristic long arm, the meromycolate chain, and a shorter arm, the alfa-alkyl chain. We are interested in clarifying the 3-dimensional atomic structures of several enzymes that form a part of the catalytic assembly line making mycolic acids. We are also interested to learn how these enzymes work with other components of the assembly line, and how this is regulated. We employ X-ray crystallography and a range of other experimental techniques, to give us details of the molecular structure of the enzymes in question, and of interactions taking place between them. Such information will provide a more complete understanding of mycolic acid synthesis and may, in the long term, aid the process of finding new therapeutics against this ancient adversary of humanity.