Novel oxadiazols for the treatment of drug-resistant gram-positive bacteria

用于治疗耐药革兰氏阳性菌的新型恶二唑类药物

• 批准号: 8692635
• 负责人: Mayland F Chang
• 金额: $ 99.05万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8692635
• 关键词: Accounting; Anti-Bacterial Agents; Antibiotics; Bacteremia; Bacterial Infections; Binding; Binding Sites; Biological Availability; Cell Wall; Cessation of life; Clinic; Complex; Computer Simulation; Development; Docking; Dose; Drug Interactions; Drug Kinetics; Drug or chemical Tissue Distribution; Drug resistance; Electronics; Enterococcus; Enzymes; Evaluation; Excretory function; Genome; Goals; Gold; Gram-Positive Bacteria; Grant; Hand; Hospitalization; Housing; In Vitro; Infection; Investigation; Laboratories; Lead; Letters; Licensing; Light; Linezolid; Medical; Metabolic; Metabolism; Methods; Modeling; Molecular; Mus; Nature; Nosocomial Infections; Organism; Penicillin-Binding Proteins; Pharmaceutical Preparations; Pharmacologic Substance; Photoaffinity Labels; Positioning Attribute; Property; Proteins; Proteome; Resistance; Resort; Rodent; Rodent Model; Safety; Skin Tissue; Soft Tissue Infections; Solubility; Staging; Staphylococcus aureus; Structure; Surgical Wound Infection; Therapeutic Index; Toxic effect; Urinary tract infection; Validation; Vancomycin; Vancomycin Resistance; Vancomycin resistant enterococcus; Virtual Library; Water; Work; absorption; base; combat; combinatorial; commercialization; drug candidate; drug resistant bacteria; human disease; in vivo; methicillin resistant Staphylococcus aureus; novel; pre-clinical; programs; resistance mechanism; screening

DESCRIPTION (provided by applicant): Staphylococcus aureus is responsible for a number of human diseases, including skin and soft tissue infections. Annually, 292,000 hospitalizations in the US are due to S. aureus infections, of which 126,000 are related to methicillin-resistant Staphylococcus aureus (MRSA), resulting in 19,000 deaths. Enterococci are the leading cause of nosocomial bacteremia, surgical wound infections, and urinary tract infections. Vancomycin-resistant enterococci (VRE) accounts for >25% of the enterococci hospital-acquired infections in the US. A novel structural lead, the oxadiazol class of antibiotics, has emerged from our work. The oxadiazol antibiotics show high in vitro potency against Gram-positive bacteria comparable to those of linezolid and superior to vancomycin (both considered gold standards) and show in vivo activity. In addition, the oxadiazols have activity against vancomycin- resistant MRSA and VRE, two organisms for which treatment options are extremely limited. The compounds in hand at this point are not highly water soluble and their pharmacokinetic properties are not optimized. This project proposes to optimize the initial lead discovery to come up with lead candidates with the correct mix of pharmacological activity, PK attributes, and safety profile, such that an oxadiazol drug candidate will be selected and advanced to preclinical development. We also propose a novel method for the identification and validation of the target(s) for the oxadiazol antibiotics in the proteome of S. aureus and put forth a whole genome method for investigation of the mechanism of resistance to this class of antibiotics. Infections caused by drug-resistant bacteria are an increasing unmet medical need. The drug of last resort, linezolid, is reserved for use in hard-to-treat methicillin-resistant S. aureus (MRSA) and vancomycin-resistant enterococci (VRE). New treatments are urgently needed to combat the emergence of resistance to any antibiotic after introduction of the antibiotic to the clinic. Our group has developed a new oxadiazol class of antibiotics that shows activity against vancomycin-resistant MRSA and VRE comparable to linezolid. Our goal is to develop a new class of antibiotics to treat drug-resistant bacterial infections.

描述（由申请人提供）：金黄色葡萄球菌是导致许多人类疾病的原因，包括皮肤和软组织感染。在美国，每年有29.2万人因金黄色葡萄球菌感染而住院，其中12.6万人与耐甲氧西林金黄色葡萄球菌（MRSA）有关，导致1.9万人死亡。肠球菌是院内菌血症、手术伤口感染和尿路感染的主要原因。在美国，万古霉素耐药肠球菌（VRE）占医院获得性肠球菌感染的25%。一种新的结构先导，恶二唑类抗生素，已经从我们的工作中出现。恶二唑抗生素对革兰氏阳性细菌的体外效力与利奈唑胺相当，优于万古霉素（两者都被认为是金标准），并显示出体内活性。此外，恶二唑对万古霉素耐药的MRSA和VRE有活性，这两种生物的治疗选择非常有限。在这一点上，手头的化合物不是高度水溶性的，它们的药代动力学性质没有优化。本项目拟优化最初的先导药物发现，以获得具有正确的药理活性、PK属性和安全性组合的候选先导药物，从而选择恶二唑候选药物并推进临床前开发。我们还提出了一种新的方法来鉴定和验证金黄色葡萄球菌蛋白质组中恶二唑类抗生素的靶点，并提出了一种全基因组方法来研究这类抗生素的耐药机制。

项目成果

The Natural Product Essramycin and Three of Its Isomers Are Devoid of Antibacterial Activity.

天然产物艾斯拉霉素及其三种异构体缺乏抗菌活性。

• DOI: 10.1021/acs.jnatprod.6b00057
• 发表时间: 2016
• 期刊: Journal of natural products
• 影响因子: 5.1
• 作者: Wang,Huan;Hesek,Dusan;Lee,Mijoon;Lastochkin,Elena;Oliver,AllenG;Chang,Mayland;Mobashery,Shahriar
• 通讯作者: Mobashery,Shahriar

Three-dimensional QSAR analysis and design of new 1,2,4-oxadiazole antibacterials.

• DOI: 10.1016/j.bmcl.2015.12.041
• 发表时间: 2016-02-01
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: Leemans E;Mahasenan KV;Kumarasiri M;Spink E;Ding D;O'Daniel PI;Boudreau MA;Lastochkin E;Testero SA;Yamaguchi T;Lee M;Hesek D;Fisher JF;Chang M;Mobashery S
• 通讯作者: Mobashery S

Exploration of the structure-activity relationship of 1,2,4-oxadiazole antibiotics.

• DOI: 10.1016/j.bmcl.2015.06.044
• 发表时间: 2015-11-01
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: Ding D;Boudreau MA;Leemans E;Spink E;Yamaguchi T;Testero SA;O'Daniel PI;Lastochkin E;Chang M;Mobashery S
• 通讯作者: Mobashery S

Mutations in mmpL and in the cell wall stress stimulon contribute to resistance to oxadiazole antibiotics in methicillin-resistant Staphylococcus aureus.

mmpL 和细胞壁应激刺激的突变导致耐甲氧西林金黄色葡萄球菌对恶二唑类抗生素产生耐药性。

• DOI: 10.1128/aac.03501-14
• 发表时间: 2014
• 期刊: Antimicrobial agents and chemotherapy
• 影响因子: 4.9
• 作者: Xiao,Qiaobin;Vakulenko,Sergei;Chang,Mayland;Mobashery,Shahriar
• 通讯作者: Mobashery,Shahriar

Discovery of a new class of non-β-lactam inhibitors of penicillin-binding proteins with Gram-positive antibacterial activity.

发现具有革兰氏阳性抗菌活性的青霉素结合蛋白的新型非β-内酰胺抑制剂。

• DOI: 10.1021/ja500053x
• 发表时间: 2014-03-05
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: O'Daniel PI;Peng Z;Pi H;Testero SA;Ding D;Spink E;Leemans E;Boudreau MA;Yamaguchi T;Schroeder VA;Wolter WR;Llarrull LI;Song W;Lastochkin E;Kumarasiri M;Antunes NT;Espahbodi M;Lichtenwalter K;Suckow MA;Vakulenko S;Mobashery S;Chang M
• 通讯作者: Chang M