Inhibitors of Staphylococcus aureus NaMN adenylyltransferase NadD

金黄色葡萄球菌 NaMN 腺苷酸转移酶 NadD 抑制剂

• 批准号: 8411585
• 负责人: ANDREI L OSTERMAN
• 金额: $ 4.73万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-15 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8411585
• 关键词: Active Sites; Address; Affinity; Anabolism; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Bacillus anthracis; Bacteria; Biogenesis; Biological Assay; Categories; Cephalosporins; Chemicals; Comparative Genomic Analysis; Complex; Computer Simulation; Development; Drug resistance; Enzymes; Escherichia coli; Essential Genes; Family; Family member; Future; Genes; Glutamate-ammonia-ligase adenylyltransferase; Goals; Gram-Negative Bacteria; Gram-Positive Bacteria; Growth; Hospitals; Human; In Vitro; Incidence; Infection; Inhibitory Concentration 50; Kinetics; Lead; Libraries; Metabolism; Methods; Modeling; Molecular Probes; Multi-Drug Resistance; National Institute of Allergy and Infectious Disease; Nicotinamide adenine dinucleotide; Nicotinate-nucleotide adenylyltransferase; Nosocomial Infections; Oxidation-Reduction; Pathway interactions; Penicillins; Property; Public Health; Recombinants; Reporting; Research Personnel; Resistance; Resort; Risk Factors; Source; Staging; Staphylococcus aureus; Testing; Validation; Vancomycin; Work; analog; antimicrobial drug; base; cofactor; combat; comparative genomics; counterscreen; falls; functional genomics; high throughput screening; improved; in vitro Assay; inhibitor/antagonist; methicillin resistant Staphylococcus aureus; nicotinate mononucleotide; novel; pathogen; prototype; resistant strain; screening; small molecule; tool

DESCRIPTION (provided by applicant): The rapid spread of multidrug-resistant strains of common bacteria pathogens pose a significant threat to public health, calling for an accelerated effort to develop novel antibiotics acting on previously unexplored targets. Most notably, many strains of Staphylococcus aureus, a major source of infections in hospitals, are resistant to commonly used antibiotics. Comparative genomics analysis and gene essentiality studies implicated nicotinic acid mononucleotide (NaMN) adenylyltransferase of the NadD family, the key indispensable enzyme in NAD biogenesis of most bacteria (including S. aureus), as a prominent target for the development of novel antimicrobial agents. In previous studies, first, small molecule inhibitors of NadD enzymes from representative gram-positive and gram-negative bacteria were identified, and then their on- target antibacterial activity was confirmed. Some of the identified compounds also showed strong inhibitory activity against S. aureus NadD enzyme. These results provided validation of the NadD target and set the stage for searching for new inhibitors with substantially improved affinity, selectivity, and antibacterial properties. This goal would be addressed in the proposed project by pursuing the following specific aims: (I) screen the MLPCN small molecule compound library and perform hit optimization to identify high-affinity inhibitors of S. aureus NadD enzyme (with IC50 d1 microM); (II) test confirmed hits by secondary assays and in the counter screen against is functional but structurally distinct human enzyme; (III) assess antibacterial properties and kinetic mechanisms of selected nominated probes. The feasibility of the proposed project is supported by the availability of the pure recombinant target enzyme as well as HTS assay methods developed in preliminary studies. Selected best inhibitors will be used in future work as molecular probes to further explore NAD biosynthesis as a target pathway for the development of novel antibiotics.

描述（由申请人提供）：多种抗性菌株的常见细菌病原体的迅速传播对公共卫生构成了重大威胁，呼吁加速努力开发针对先前未开发的靶标作用的新型抗生素。最值得注意的是，许多葡萄球菌金黄色葡萄球菌菌株（医院的主要感染来源）对常用抗生素具有抗性。比较基因组学分析和基因本质研究暗示了NADD家族的烟酸单核苷酸（NAMN）腺苷转移酶，这是大多数细菌的NAD生物发生中的主要必不可少的酶（包括金黄色葡萄球菌），是新型抗微生物型抗菌剂的重要靶标。在先前的研究中，首先鉴定了来自代表性革兰氏阳性和革兰氏阴性细菌的NADD酶的小分子抑制剂，然后证实了其对靶抗菌活性。一些已鉴定的化合物还显示出对金黄色葡萄球菌NADD酶的强抑制活性。这些结果提供了NADD目标的验证，并为寻找具有显着改善亲和力，选择性和抗菌特性的新抑制剂奠定了基础。 该目标将通过追求以下特定目的来解决该目标：（i）筛选MLPCN小分子化合物库，并执行HIT HIT优化以识别金黄色葡萄球菌NADD酶的高亲和力抑制剂（使用IC50 D1 microm）； （ii）测试通过次级测定确认命中，在计数器屏幕上是功能性但结构上不同的人类酶； （iii）评估选定提名探针的抗菌特性和动力学机制。拟议项目的可行性得到了纯重组靶酶以及初步研究中开发的HTS测定方法的可用性。选定的最佳抑制剂将在将来的工作中用作分子探针，以进一步探索NAD生物合成，作为开发新抗生素的靶标途径。