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性的公共卫生问题。新出现的结核杆菌菌株（结核分枝杆菌）对当今的一种或几种抗结核药物产生了耐药性，使问题变得更糟。迫切需要新的和更有效的治疗选择来控制结核病。自科赫时代以来，M.结核病和相关的生物体因其周围有一层厚厚的蜡状包膜而闻名。该细胞被膜包含高度组织化的层状结构中的脂质、多糖和肽组分。我们部分地理解了这些成分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。这项提案的重点是细胞包膜的一种成分，称为分枝菌酸，它占结核杆菌生物量的10%，是生存所必需的。分枝菌酸是一种特殊类型的脂肪酸，其包含特征性的长臂（部分分枝菌酸酯链）和较短的臂（α-烷基链）。我们有兴趣澄清的三维原子结构的几种酶，形成催化装配线的一部分，使分枝菌酸。我们也有兴趣了解这些酶如何与装配线的其他组件一起工作，以及如何进行调节。我们采用X射线晶体学和一系列其他实验技术，为我们提供有关酶的分子结构以及它们之间发生的相互作用的细节。这些信息将提供对分枝菌酸合成的更完整的理解，并且从长远来看，可能有助于寻找新的治疗方法来对抗人类的这一古老对手。

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.