De Novo Synthesis, and Functional and Structural Characterization of Novel Aminoglycoside Analogues to Bypass Resistance Mechanisms and Optimize Selectivity

新型氨基糖苷类似物的从头合成、功能和结构表征，以绕过耐药机制并优化选择性

• 批准号: 10676201
• 负责人: JAMES E KIRBY
• 金额: $ 75.72万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-20 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10676201
• 关键词: Acinetobacter baumannii; Acylation; Address; Amines; Amino Sugars; Aminoglycoside Antibiotics; Aminoglycoside resistance; Aminoglycosides; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotic Resistance; Antibiotics; Bypass; Carbohydrate Chemistry; Carbohydrates; Categories; Charge; Chemicals; Coupled; Cryoelectron Microscopy; Diamines; ESKAPE pathogens; Enzymes; Event; Frequencies; Goals; Hydrogen Bonding; Hydroxyl Radical; Incidence; Infection; Laboratories; Mediating; Metabolism; Methodology; Methylation; Methyltransferase; Microbiology; Modification; Multi-Drug Resistance; Organism; Outcome; Parents; Pharmaceutical Chemistry; Positioning Attribute; Pseudomonas aeruginosa; Pyrimidine; Pyrimidines; Resistance; Ribosomes; Route; Scheme; Site; Site-Directed Mutagenesis; Structure; Structure-Activity Relationship; Therapeutic; Variant; analog; antimicrobial; bacterial resistance; bactericide; base; carbapenem-resistant Enterobacteriaceae; carbohydrate structure; clinically relevant; design; emerging antimicrobial resistance; empowerment; expectation; improved; multi-drug resistant pathogen; nephrotoxicity; novel; ototoxicity; pathogen; pathogenic bacteria; polyol; preservation; protonation; pyridine; resistance mechanism; stereochemistry; structural biology; sugar; targeted treatment; tv watching

There is an emerging threat from multidrug-resistant Gram-negative bacterial pathogens, specifically, carbapenem-resistant Enterobacteriaceae, Acinetobacter baumannii, and Pseudomonas aeruginosa (e.g., ESKAPE pathogens). The resulting infections are often untreatable or treatable only with toxic antimicrobials. More troubling is the fact that the incidences of these infections are occurring with increasing frequency. Therefore, the CDC now categorizes such organisms in their top antibiotic resistance threat level. New anti-infective strategies are urgently needed. This multi-PI R01 application proposes a de novo medicinal chemistry design and de novo carbohydrate synthesis approach, which when coupled with functional characterization and cryo-EM enabled structure-guided design should lead to the rapid discovery of novel aminoglycoside (AG) antimicrobials with activity against resistant Gram-negative pathogens. The long-term expected outcomes are 1) the establishment of new synthetic methodology for systematic medicinal chemistry SAR-based exploration of the aminoglycoside chemical space and 2) the discovery of new aminoglycoside structural motifs with improved activity against resistant bacteria (e.g., AME, RMT- mediated resistance). The underlying hypothesis that guides our approach is the assumption that there are many carbohydrate structures that remain undiscovered due to the synthetic limitations of traditional carbohydrate and semi-synthetic approaches. In contrast, our total de novo synthetic approach enables the installation of a much broader range of carbohydrates in a stereochemically selective manner. Examples of structural variations that will be explored are aminoglycosides with rare aminosugar, linear sugar, and 2- deoxystreptamine (2-DOS) substitutions that are designed to evade known aminoglycoside resistance mechanisms.

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项目成果

Structure-activity relationship of avocadyne.

• DOI: 10.1039/d1fo00693b
• 发表时间: 2021-07-21
• 期刊: Food & function
• 影响因子: 6.1
• 作者: Tcheng M ;Cunha VLS ;Ahmed N ;Liu X ;Smith RW ;Rea KA ;Akhtar TA ;D'Alessandro A ;Minden MD ;Vockley J ;O'Doherty GA ;Lowary TL ;Spagnuolo PA
• 通讯作者: Spagnuolo PA

De novo asymmetric Achmatowicz approach to oligosaccharide natural products.

• DOI: 10.1039/d2cc05280f
• 发表时间: 2022-11-22
• 期刊: CHEMICAL COMMUNICATIONS
• 影响因子: 4.9
• 作者: Kim, Sugyeom;Oiler, Jeremy;Xing, Yalan;O'Doherty, George A.
• 通讯作者: O'Doherty, George A.

Identifying requirements for RSK2 specific inhibitors.

确定对RSK2特异性抑制剂的要求。

• DOI: 10.1080/14756366.2021.1957862
• 发表时间: 2021-12
• 期刊: Journal of enzyme inhibition and medicinal chemistry
• 影响因子: 5.6
• 作者: Wright EB;Fukuda S;Li M;Li Y;O'Doherty GA;Lannigan DA
• 通讯作者: Lannigan DA

Stereoselective Synthesis of β-Glycinamide Ribonucleotide.

• DOI: 10.3390/molecules27082528
• 发表时间: 2022-04-14
• 期刊: MOLECULES
• 影响因子: 4.6
• 作者: Ngu, Lisa;Ray, Debarpita;Watson, Samantha S.;Beuning, Penny J.;Ondrechen, Mary Jo;O'Doherty, George A.
• 通讯作者: O'Doherty, George A.