Inhibitors of Staphylococcus aureus NaMN adenylyltransferase NadD

描述（由申请人提供）：常见细菌病原体的多重耐药菌株的迅速传播对公共卫生构成了重大威胁，要求加快努力开发新的抗生素，作用于以前未探索的目标。最值得注意的是，许多金黄色葡萄球菌菌株对常用抗生素具有耐药性，金黄色葡萄球菌是医院感染的主要来源。比较基因组学分析和基因必要性研究表明，NadD家族的烟酸单核苷酸（NaMN）腺苷基转移酶是大多数细菌（包括金黄色葡萄球菌）NAD生物发生中不可或缺的关键酶，是开发新型抗菌药物的重要靶点。在以往的研究中，首先从具有代表性的革兰氏阳性菌和革兰氏阴性菌中鉴定出NadD酶的小分子抑制剂，然后确定其靶向抗菌活性。部分化合物对金黄色葡萄球菌NadD酶也有较强的抑制活性。这些结果验证了NadD靶点，并为寻找具有显著提高亲和力、选择性和抗菌性能的新抑制剂奠定了基础。

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.