Novel Antimicrobials Targeting Cell Division

针对细胞分裂的新型抗菌剂

• 批准号: 7739500
• 负责人: IWAO OJIMA
• 金额: $ 37.91万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7739500
• 关键词: Animal Model; Anti-Bacterial Agents; Antibiotics; Antineoplastic Agents; Bacteria; Benzimidazoles; Binding Sites; Biological Availability; Biology; Categories; Cell division; Cells; Chemicals; Colorado; Development; Drug Resistant Tuberculosis; Drug resistance; Emerging Communicable Diseases; Enterococcus; Extreme drug resistant tuberculosis; Gene Dosage; Growth; Homologous Gene; Human; Immunocompromised Host; In Vitro; Incidence; Individual; Infection; Institutes; Investigation; Laboratories; Lead; Libraries; Life; Microtubules; Multi-Drug Resistance; Multidrug-Resistant Tuberculosis; Mus; Mycobacterium tuberculosis; Patients; Pharmaceutical Preparations; Phenotype; Photoaffinity Labels; Principal Investigator; Process; Property; Protein Binding; Proteins; Resistance; Role; Screening procedure; Sequence Homology; Site; Staphylococcus aureus; Taxane Compound; Therapeutic; Toxic effect; Tubulin; Universities; Validation; X-Ray Crystallography; antimicrobial; antimicrobial drug; bacterial resistance; benzimidazole; benzimidazole analog; cytotoxic; cytotoxicity; depolymerization; design; drug candidate; drug discovery; efficacy evaluation; in vitro activity; in vivo; methicillin resistant Staphylococcus aureus; novel; pathogen; polymerization; public health relevance; research study; resistant strain; taxane; tubulin polymerization inhibitor

DESCRIPTION (provided by applicant): It is evident that the widespread misuse of antimicrobial drugs has caused bacterial resistance to all classes of antibiotics. At present, one of the most serious problems worldwide is the multi-drug resistant tuberculosis (MDR-TB), which is classified as an emerging infectious disease threat and a category C priority pathogen by NIAID/NIH. In addition, the recent emergence of extensively drug resistant strains of TB (XDR-TB) that are resistant to both first and second line drugs is even more alarming. Another threat is the infections due to drug-resistant Enterococci (VRE) and Staphylococcus aureus (MRSA), which are serious problems in hospitalized or immunocompromised individuals. There has been a rapid increase in the incidence of VRE infections, as well as a dramatic increase in the incidence of MRSA infections. Unfortunately, at present, there are only very limited therapeutic options available for patients with these infections. Therefore, there is an urgent need for the development of novel antimicrobials against new targets essential for growth, whose inhibition should give a lethal phenotype. Thus, we have selected FtsZ, the tubulin homologue in bacterial cells and essential to bacterial cell division, as the specific target to develop a new class of antimicrobial agents. The bacterial tubulin homologue FtsZ is an essential cell-division protein in bacteria that polymerizes in a GTP-dependent manner, forming a cytokinetic ring at the septum site. Accordingly, FtsZ is a very promising target for discovery and development of new broad-spectrum antimicrobial drugs because of its central role in bacterial cell division. The Principal Investigator (PI) has expertise in anticancer agents targeting tubulin/microtubules and has hypothesized that a certain class of taxanes (microtubule-stabilizer) and benzimidazoles (tubulin polymerization inhibitors) should inhibit the depolymerization or polymerization of FtsZ from Mycobacterium tuberculosis (MTB), MRSA and VRE. The fact that the sequence homology between FtsZ and tubulin is low (<20% identity) strongly indicates an excellent possibility in discovering FtsZ-specific taxanes and benzimidazoles that are non-cytotoxic to human host cells. Building upon highly encouraging preliminary results, the following specific aims will be investigated: (1) Design, Synthesis, Screening and Optimization of Taxanes and Benzimidazoles (2) Investigation into the Mechanism of Action in vitro (3) Investigation into the Mechanism of Action in Live Cells (4) In vivo Efficacy Evaluation with Animal Models Highly integrated collaborative activities will be performed through close cooperation between the Institute for Chemical Biology and Drug Discovery (ICB&DD) at Stony Brook University and The Mycobacteriology Laboratory at Colorado State University. PUBLIC HEALTH RELEVANCE: Multi-drug resistant and extensively drug resistant tuberculosis (MDR-TB and XDR-TB) are classified as an emerging infectious disease threat and category C priority pathogens by NIAID/NIH. Another emerging threat is the infections due to drug-resistant Staphylococcus aureus (MRSA) and Enterococci (VRE), which are serious problems in hospitalized or immunocompromised individuals. Unfortunately, at present, there are only very limited therapeutic options available for patients with these infections. Therefore, there is an urgent need for the development of novel antimicrobials against new targets essential for growth, whose inhibition should give a lethal phenotype. Thus, we have selected FtsZ, the tubulin homologue in bacterial cells and essential to bacterial cell division, as the specific target to develop a new class of antimicrobial agents.

描述(申请人提供)：很明显，抗菌药物的广泛滥用已导致细菌对所有类别的抗生素产生抗药性。目前，世界范围内最严重的问题之一是耐多药结核病(MDR-TB)，它被NIAID/NIH列为一种新的传染病威胁和C类优先病原体。此外，最近出现了对一线和二线药物都有耐药性的广泛耐药结核病(XDR-TB)菌株，这甚至更令人担忧。另一个威胁是耐药肠球菌(VRE)和金黄色葡萄球菌(MRSA)的感染，这是住院或免疫功能低下的人的严重问题。VRE感染的发病率迅速增加，耐甲氧西林金黄色葡萄球菌感染的发病率也急剧增加。不幸的是，目前对这些感染患者的治疗选择非常有限。因此，迫切需要开发针对生长必需的新靶点的新型抗菌剂，其抑制应该会产生致命的表型。因此，我们选择了细菌细胞中的微管蛋白同源物、细菌细胞分裂所必需的FtsZ作为开发一类新的抗菌剂的特定靶点。细菌微管蛋白同源物FtsZ是细菌中一种重要的细胞分裂蛋白，它以依赖于GTP的方式聚合，在隔部位形成一个细胞动力学环。因此，FtsZ是发现和开发新的广谱抗菌药物的一个非常有前途的靶点，因为它在细菌细胞分裂中发挥着核心作用。首席调查员(PI)在针对微管/微管的抗癌药物方面拥有专业知识，并假设某类紫杉烷(微管稳定剂)和苯并咪唑(微管聚合抑制剂)应该抑制结核分枝杆菌(MTB)、MRSA和VRE的FtsZ的解聚或聚合。FtsZ和微管蛋白之间的序列同源性很低(同源性为20%)，这一事实强烈表明，很有可能发现FtsZ特异的紫杉烷和苯并咪唑类化合物，这些化合物对人体宿主细胞没有细胞毒性。在取得令人鼓舞的初步结果的基础上，将研究以下具体目标：(1)紫杉烷和苯并咪唑类化合物的设计、合成、筛选和优化(2)体外作用机理研究(3)在活细胞中的作用机理研究(4)用动物模型进行体内疗效评估(4)石溪大学化学生物学和药物发现研究所(ICB&DD)将与科罗拉多州立大学的分枝杆菌实验室密切合作开展高度整合的协作活动。 公共卫生相关性：耐多药和广泛耐药结核病(MDR-TB和XDR-TB)被NIAID/NIH列为新出现的传染病威胁和C类优先病原体。另一个新出现的威胁是由耐药金黄色葡萄球菌(MRSA)和肠球菌(VRE)引起的感染，这是住院或免疫功能低下的人的严重问题。不幸的是，目前对这些感染患者的治疗选择非常有限。因此，迫切需要开发针对生长必需的新靶点的新型抗菌剂，其抑制应该会产生致命的表型。因此，我们选择了细菌细胞中的微管蛋白同源物、细菌细胞分裂所必需的FtsZ作为开发一类新的抗菌剂的特定靶点。