Thiolactomycin Acid Derivatives as Novel Antibacterials

硫代乳霉素酸衍生物作为新型抗菌药

• 批准号: 6325212
• 负责人: KEN DUNCAN
• 金额: $ 121.13万
• 依托单位: GLAXOSMITHKLINE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2005-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6325212
• 关键词: Mycobacterium tuberculosis; Staphylococcus aureus; antibacterial agents; biotechnology; combinatorial chemistry; drug discovery /isolation; high throughput technology; laboratory mouse; lactones

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.

原核脂肪酸生物合成途径为选择性抗菌药物的开发提供了重要的新靶点。本研究的总体目标是开发一种新型的口服生物可利用的、可开发的临床前先导分子，这些先导分子是细菌b-酮酰基- acp合成酶的有效特异性抑制剂，并具有抗多重耐药结核分枝杆菌（MDRTB）、金黄色葡萄球菌（MRSA）和肠球菌（VRE）的抗菌活性。这些新型抗生素将通过利用FabB与硫代戊酸硫代霉素（TLM）络合的三维结构设计的集中组合化学文库来获得。硫霉素是一个很好的候选者，在此基础上建立一个优化策略。TLM对目标生物的体内和体外抗菌活性已经被证明，它具有与口服生物可利用性和无毒相容的物理化学特性。为了达到所需的治疗产品特性，需要提高生物活性，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。硫霉素从未成为此类药物化学项目的主题。b-酮酰基- acp合成酶将从关键病原体中克隆、表达、纯化和结晶，包括上述病原体，并进行配置以允许高通量筛选TLM类似物的检测。强有力的线索将是最先进的机制酶学，驱动SAR的共晶学研究，体外和体内抗菌测试以及初步药代动力学分析的主题，以最大限度地产生和优化真正的候选药物。另一个好处是，这些药物对目前主要的抗生素耐药机制不敏感。细菌b型酮酰基- acp合成酶也存在于疟疾和其他顶复合体寄生虫以及锥虫中。有一个明显的可能性，这些严重的病原体可能包括在新的TLM类似物的活性谱。SmithKline Beecham拥有世界领先的抗生素专营权，在推动新型抗菌药物的发展方面具有独特的地位。