Synthesis and Evaluation of Narrow-Spectrum Antibiotics Targeting MRSA

针对MRSA的窄谱抗生素的合成与评价

• 批准号: 9981542
• 负责人: RODRIGO B ANDRADE
• 金额: $ 14.5万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9981542
• 关键词: Address; Alkynes; American; Aminoglycosides; Anabolism; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Bacterial Antibiotic Resistance; Bacterial Infections; Biochemical; Biochemistry; Biological; Biological Assay; Cell Wall; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Chemicals; Chemistry; Clinical; Colistin; Complex; Coupled; Crystallization; Data; Development; Escherichia coli; Evaluation; Genes; Genomic approach; Goals; Human; Label; Libraries; Light; Macrolides; Medicine; Metabolic; Methodology; Methods; Minimum Inhibitory Concentration measurement; Modification; Molecular Biology; Natural Products; Organism; Patients; Peptidoglycan; Pharmacologic Substance; Pharmacopoeias; Property; Proteomics; Reporting; Resistance; Resistance development; Resort; Risk; Roentgen Rays; Septic Shock; Staphylococcus aureus; Structure; Structure-Activity Relationship; Superbug; Testing; Tetracyclines; Vancomycin; Vancomycin-resistant S. aureus; activity-based protein profiling; adduct; analog; bacterial resistance; base; beta-Lactams; computational chemistry; cytotoxicity; design; falls; genome sequencing; global health; improved; inhibitor/antagonist; lead candidate; methicillin resistant Staphylococcus aureus; molecular modeling; mutant; novel; novel therapeutics; pathogenic bacteria; resistance frequency; response; scaffold; septic patients; tool; whole genome

Project Summary/Abstract Natural products account for two-thirds of the antibacterial pharmacopeia and are therefore privileged scaffolds. These complex molecules have inspired novel synthetic methods and positively impacted the fields of biochemistry, molecular biology, and medicine. The proposed project is inspired by albocycline, a unique 14-membered macrolactone with potent, narrow-spectrum activity against the “superbug” methicillin- resistant Staphylococcus aureus (MRSA). We have validated that albocycline is effective against MRSA and vancomycin-resistant S. aureus strains; moreover, it is non-toxic to human cells. In 2013, Tomoda reported that albocycline inhibited peptidoglycan (i.e., bacterial cell wall) synthesis in macromolecular assays. Using biochemical assays and molecular modeling, we demonstrated that albocycline was a weak (mM) inhibitor of MurA from S. aureus. Consistent with its narrow-spectrum profile, albocycline did not inhibit MurA from E. coli. Based on our results and those of Tomoda, we conclude it must have additional bacterial targets. Significantly, we recently completed a modular, step-efficient total synthesis of the natural product driven by novel chemistry of N-sulfinyl metallodienamines. Accordingly, in Aim 1 we propose to prepare albocycline analogs (including probes) by semi- and diverted total synthesis to explore the chemical space about this privileged scaffold. In Aim 2, we will co-crystallize albocycline in complex with MurA based on exciting preliminary results and employ structure-based analog design. We will also identify the target(s) of albocycline to determine its mode-of-action using computational chemistry, chemical proteomics and genomics approaches, in addition to a novel metabolic labeling methodology. Finally, in Aim 3 we will evaluate the biological activity of all albocycline analogs. At the end of the four-year project period, we will have (1) a deeper understanding of how albocycline exerts its antibacterial action; (2) a library of tool compounds and antibiotic lead candidates that selectively modulate their target(s); and most significantly, (3) a bona fide launching point for the development of novel, narrow-spectrum antibiotics to treat recalcitrant MRSA, VISA, and VRSA (i.e., the project's long-term goal).

项目总结/摘要 天然产品占抗菌药物药典的三分之二，因此享有特权 脚手架这些复杂的分子激发了新的合成方法，并对这些领域产生了积极的影响。 生物化学、分子生物学和医学。该拟议项目的灵感来自白环素，一种 独特的14元大环内酯，对“超级细菌”甲氧西林具有强效、窄谱活性， 耐药金黄色葡萄球菌（MRSA）。我们已经验证了albocycline对MRSA有效， 万古霉素抗性S.金黄色葡萄球菌菌株;此外，它对人体细胞无毒。 2013年，Tomoda报道了白霉素抑制肽聚糖（即，细菌细胞壁）合成 大分子测定使用生化测定和分子建模，我们证明白环素 是一个弱的（mM）抑制剂的MurA从S。金黄色。与其窄谱特征一致， 对E.杆菌根据我们的结果和Tomoda的结果，我们得出结论，它必须有额外的 细菌目标。值得注意的是，我们最近完成了一个模块化的，步骤有效的天然全合成， 由N-亚磺酰基金属二烯胺的新化学驱动的产物。因此，在目标1中，我们建议 通过半合成和转向全合成制备albocycline类似物（包括探针），以探索化学 这个特殊的脚手架周围的空间。在目标2中，我们将基于以下共结晶与MurA复合的白环素： 令人兴奋的初步结果，并采用基于结构的模拟设计。我们亦会确定以下的目标： 使用计算化学、化学蛋白质组学和基因组学确定其作用模式 方法，除了一种新的代谢标记方法。最后，在目标3中，我们将评估 所有albocycline类似物的生物活性。 在四年的项目期结束时，我们将有（1）更深入的了解如何albocycline 发挥其抗菌作用;（2）工具化合物和抗生素先导候选物库， 调整他们的目标;最重要的是，（3）小说发展的真正起点， 窄谱抗生素治疗耐药MRSA、VISA和VRSA（即，项目的长期目标）。

项目成果

Synthesis and biological evaluation of semi-synthetic albocycline analogs.

• DOI: 10.1016/j.bmcl.2020.127509
• 发表时间: 2020-11-01
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: Daher SS;Franklin KP;Scherzi T;Dunman PM;Andrade RB
• 通讯作者: Andrade RB

Alternative approaches utilizing click chemistry to develop next-generation analogs of solithromycin.

• DOI: 10.1016/j.ejmech.2022.114213
• 发表时间: 2022-04-05
• 期刊: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 6.7
• 作者: Daher, Samer S.;Lee, Miseon;Jin, Xiao;Teijaro, Christiana N. N.;Barnett, Pamela R. R.;Freundlich, Joel S. S.;Andrade, Rodrigo B. B.
• 通讯作者: Andrade, Rodrigo B. B.

Staphylococcus aureus resistance to albocycline can be achieved by mutations that alter cellular NAD/PH pools.

• DOI: 10.1016/j.bmc.2021.115995
• 发表时间: 2021-02-15
• 期刊: Bioorganic & medicinal chemistry
• 影响因子: 3.5
• 作者: Scherzi T;D'Ambrosio EA;Daher SS;Grimes CL;Dunman PM;Andrade RB
• 通讯作者: Andrade RB