Novel Antimicrobials Targeting Cell Division

描述（由申请人提供）：很明显，抗菌药物的广泛滥用已经导致细菌对所有类别的抗生素产生耐药性。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列为新兴传染病威胁和C类重点病原体。此外，最近出现的对一线和二线药物都具有耐药性的广泛耐药结核（XDR-TB）菌株更加令人震惊。另一个威胁是由耐药肠球菌（VRE）和金黄色葡萄球菌（MRSA）引起的感染，这对住院或免疫功能低下的个体来说是严重的问题。VRE感染的发生率迅速增加，MRSA感染的发生率也急剧增加。不幸的是，目前，只有非常有限的治疗方案可用于这些感染的患者。因此，迫切需要开发针对生长所必需的新靶点的新型抗菌剂，其抑制应产生致死表型。因此，我们选择细菌细胞中的微管蛋白同系物、细菌细胞分裂所必需的FtsZ作为开发一类新型抗菌药物的特异性靶点。细菌微管蛋白同源物FtsZ是细菌中必需的细胞分裂蛋白，以gtp依赖的方式聚合，在隔膜部位形成细胞动力学环。因此，由于FtsZ在细菌细胞分裂中的核心作用，它是发现和开发新的广谱抗菌药物的一个非常有希望的靶点。首席研究员（PI）在针对微管蛋白/微管的抗癌药物方面具有专业知识，并假设某一类紫杉烷（微管稳定剂）和苯并咪唑（微管蛋白聚合抑制剂）应该抑制结核分枝杆菌（MTB）， MRSA和VRE的FtsZ解聚或聚合。FtsZ与微管蛋白之间的序列同源性较低（同源性<20%），这一事实强烈表明，发现对人类宿主细胞无细胞毒性的FtsZ特异性紫杉烷和苯并咪唑具有很大的可能性。在非常令人鼓舞的初步结果的基础上，将调查下列具体目标：(1)紫杉烷类和苯并咪唑类药物的设计、合成、筛选与优化(2)体外作用机制的研究(3)活细胞作用机制的研究(4)动物模型的体内疗效评价（动物模型）高度整合的合作活动将通过石溪大学化学生物学与药物发现研究所（ICB&DD）和科罗拉多州立大学分枝杆菌学实验室的密切合作进行。

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.