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/文摘

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