Discovery of Novel Macrolide Antibiotics

新型大环内酯类抗生素的发现

基本信息

批准号：
8288248
负责人：
RODRIGO B ANDRADE
金额：
$ 34.95万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-15 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8288248
关键词：
Address Affinity Antibiotic Resistance Antibiotics Architecture Azithromycin Bacteria Bacterial Antibiotic Resistance Binding Biological Biological Assay Biological Factors Chemistry Clinic Complex Computer Assisted Computer Simulation Drug Design Drug Kinetics Drug effect disorder Drug resistance Economics Erythromycin Escherichia coli Future Generations Goals Gram-Positive Bacteria Guanosine Hydrogen Ketolides Laboratories Libraries Ligands Macrolide Antibiotics Macrolides Measures Methodology Methods Minimum Inhibitory Concentration measurement Molecular Molecular Conformation Mutation Pharmaceutical Preparations Pharmacologic Substance Positioning Attribute Property Protein Biosynthesis Public Health Research Resistance Resources Ribonucleotides Ribosomal RNA Ribosomes Role Route Scheme Side Source Structure Testing Virtual Library Work analog antimicrobial attenuation bacterial resistance bactericide base chemical synthesis design desosamine efficacy testing in vivo insight interest meetings methicillin resistant Staphylococcus aureus methyl group novel pressure prevent programs pyranose research clinical testing resistance mechanism scaffold success telithromycin tool

项目摘要

Project Summary The rapid and incessant rise in antibiotic-resistant bacteria represents a serious public health threat that must be addressed.1 Economic pressures have resulted in an overall decrease in the number of pharmaceutical companies with active antimicrobial research programs, underscoring the need for new sources of antibiotics.2 The broad, long-term goal of the proposed work is to meet this need by discovering novel macrolide antibiotics that directly address known resistance mechanisms by rational drug design. The mechanism of macrolide antibiotic drug action is known.3 These drugs bind the bacterial ribosome and prevent protein synthesis. Recently, crystal structures of various macrolide drugs (e.g., erythromycin, telithromycin, azithromycin) bound to ribosomal subunits have been solved, offering valuable structural insight as to how these compounds bind (i.e., contact with ribonucleotide residues) and how resistance mechanisms undermine drug action.4 Resistance mechanisms in which the ribosome itself is modified represent a formidable challenge to medicinal chemists.5 To address these particular mechanisms and facilitate chemical synthesis, the paradigm of natural product structure simplification (molecular editing)6 will be applied to the ketolide telithromycin, a 3rd generation semisynthetic drug derived from the flagship macrolide antibiotic erythromycin A and used in the clinic since 2004.7 Aims include (1) the application of computer-aided drug design (CADD) tools that will first evaluate a virtual library of selected macrolide analogues bound to both wild-type and resistant ribosomal subunits to determine the candidates most likely to have bioactivity and overcome resistance. In tandem, (2) chemical synthesis featuring novel methodology will provide access to material, which will (3) be screened against drug-susceptible and drug-resistant bacterial strains. This will serve to test the hypothesis that structural simplification of the complex macrolide architecture will directly address resistance without compromising bioactivity. Another round of CADD will serve to optimize the most promising candidates. Bioassays will measure success in this endeavor.

项目摘要抗生素耐药细菌的迅速和不断增加代表了严重的公共卫生威胁必须解决这一问题。1经济压力导致数量的总体减少具有活跃抗菌研究计划的制药公司，强调了对 2 发现新型的大环内酯类抗生素，该抗生素直接解决已知的抗性机制理性药物设计。大花环抗生素药物作用的机制。3这些药物结合细菌核糖体并预防蛋白质合成。最近，各种大环内酯类药物的晶体结构（例如红霉素，丝霉素，阿奇霉素与核糖体亚基结合，提供关于这些化合物如何结合的宝贵结构见解（即与核糖核苷酸残基接触）以及耐药机制如何破坏药物作用。4抗性机制，其中核糖体本身经过修改代表了对药物学家的巨大挑战。5解决这些问题特定的机制并促进化学合成，自然产物结构的范式简化（分子编辑）6将应用于第三代的酮底素丝霉素源自旗舰大环内酯类抗生素红霉素A的半合成药物，用于诊所自2004年以来目的包括（1）使用计算机辅助药物设计（CADD）工具，该工具将首先评估与野生型和抗性核糖体结合的精选大花环类似物的虚拟库确定最有可能具有生物活性并克服抵抗力的候选人的亚基。在串联，（2）具有新方法的化学合成将提供对材料的访问，这将（3）应筛选对药物敏感和耐药细菌菌株的筛查。这将用于测试复杂的大花环体系结构的结构简化将直接解决的假设耐药性而不会损害生物活性。另一轮CADD将有助于优化最多有希望的候选人。生物测定将衡量这项努力的成功。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Desmethyl Macrolide Analogues to Address Antibiotic Resistance: Total Synthesis and Biological Evaluation of 4,8,10-Tridesmethyl Telithromycin.

DOI：
10.1021/ml1002184
发表时间：
2011-01-13
期刊：
ACS MEDICINAL CHEMISTRY LETTERS
影响因子：
4.2
作者：
Velvadapu, Venkata;Paul, Tapas;Wagh, Bharat;Klepacki, Dorota;Guvench, Olgun;MacKerell, Alexander, Jr.;Andrade, Rodrigo B.
通讯作者：
Andrade, Rodrigo B.

Desmethyl Macrolides: Synthesis and Evaluation of 4,8,10-Tridesmethyl Cethromycin.

DOI：
10.1021/ml400337t
发表时间：
2013-11-14
期刊：
ACS medicinal chemistry letters
影响因子：
4.2
作者：
Wagh B;Paul T;Debrosse C;Klepacki D;Small MC;Mackerell AD Jr;Andrade RB
通讯作者：
Andrade RB

Total synthesis of (-)-4,8,10-tridesmethyl telithromycin.

DOI：
10.1021/jo201319b
发表时间：
2011-09-16
期刊：
JOURNAL OF ORGANIC CHEMISTRY
影响因子：
3.6
作者：
Velvadapu, Venkata;Paul, Tapas;Wagh, Bharat;Glassford, Ian;DeBrosse, Charles;Andrade, Rodrigo B.
通讯作者：
Andrade, Rodrigo B.

Desmethyl Macrolides: Synthesis and Evaluation of 4,10-Didesmethyl Telithromycin.

DOI：
10.1021/ml200254h
发表时间：
2012-03-08
期刊：
ACS MEDICINAL CHEMISTRY LETTERS
影响因子：
4.2
作者：
Velvadapu, Venkata;Glassford, Ian;Lee, Miseon;Paul, Tapas;DeBrosse, Charles;Klepacki, Dorota;Small, Meagan C.;MacKerell, Alexander D., Jr.;Andrade, Rodrigo B.
通讯作者：
Andrade, Rodrigo B.