Thiolactomycin Acid Derivatives as Novel Antibacterials

原核脂肪酸生物合成途径构成了一个潜在的丰富来源的基本和新的目标选择性抗菌药物的发展。本提案的总体目标是开发一类新型的口服生物可利用的、可开发的临床前先导分子，其是细菌b-酮酰基-ACP糖苷酶的有效和特异性抑制剂，并对多重耐药结核分枝杆菌（MDRTB）、金黄色葡萄球菌（MRSA）和肠球菌（VRE）具有抗菌活性。这些新型抗生素将通过构建聚焦组合化学文库来获得，所述聚焦组合化学文库使用与硫代特窗酸硫代乳霉素（TLM）复合的FabB的三维结构来设计。硫乳霉素是一个很好的候选人，基于优化策略。TLM对靶生物的体外和体内抗菌活性已得到证实，并且已显示其具有与口服生物利用度相容的理化性质且无毒。为了获得所需的治疗产品特征，需要改善生物活性，我们已经多次证明，这些可以通过密集的组合和阵列化学与基于结构的设计相结合来实现。硫乳霉素从来没有这样的药物化学计划的主题。将从关键病原体（包括上述病原体）克隆、表达、纯化和结晶B-酮脂酰-ACP脱氢酶，并进行配置以允许高通量筛选TLM类似物的测定。有效的先导物将成为最先进的机制酶学、共晶体学研究的主题，以驱动SAR、体外和体内抗菌测试以及初步药代动力学分析，以最大限度地生成和优化真正的候选药物。另一个优势是，这些药物对目前主要的抗生素耐药机制不敏感。细菌型B-酮脂酰-ACP脱氢酶也存在于疟疾和其他顶复门寄生虫以及锥虫中。这些严重的病原体可能包含在新型TLM类似物的活性谱中，这是一种明显的可能性。史克必成拥有世界领先的抗生素专营权，在推动新型抗菌药物的开发方面具有独特的优势。

The prokaryotic fatty acid biosynthesis pathway constitutes a potentially rich source of essential and novel targets for selective antibacterial drug development. The overall aim of this proposal is to develop a novel class of orally bioavailable, developable preclinical lead molecules that are potent and specific inhibitors of bacterial b-ketoacyl-ACP synthases and possess antibacterial activity against multi-drug resistant Mycobacterium tuberculosis (MDRTB), Staphylococcus aureus (MRSA) and enterococci (VRE). These novel antibiotics will be obtained by the construction of focused combinatorial chemical libraries designed using the three- dimensional structure of FabB complexed with the thiotetronic acid thiolactomycin (TLM). Thiolactomycin is an excellent candidate upon which to base an optimization strategy. In vitro and in vivo antibacterial activity have already been demonstrated for TLM against the target organisms and it has been shown to have physicochemical properties compatible with being orally bioavailable and non-toxic. In order to achieve-the required therapeutic product profile, improvements in biological activity are required and we have demonstrated numerous times that these can be achieved by intensive combinatorial and array chemistry in combination with structure-based design. Thiolactomycin has never been the subject of such a medicinal chemistry program. b- ketoacyl-ACP synthases will be cloned, expressed, purified and crystallized from key pathogens, including the above, and assays configured to permit high throughput screening of TLM analogues. Potent leads will be the subject of state-of-the-art mechanistic enzymology, cocrystallography studies to drive SAR, in vitro and in vivo antibacterial testing and preliminary pharmacokinetic analysis to maximize the generation and optimization of genuine drug candidates. An added advantage accrues because such drugs would be insensitive to current major antibiotic resistance mechanisms. Bacterial type b- ketoacyl-ACP synthases are also present in malaria and other Apicomplexan parasites, as well as Trypanosomes. There is a distinct possibility that these serious pathogens may be included in the spectrum of activity of novel TLM analogues. SmithKline Beecham has a world- leading antibiotic franchise and is uniquely placed to drive the development of novel classes of antibacterial drugs.