Identification and Characterization of Novel Antimicrobial Adjunctives to Restore Susceptibility to Carbapenem Resistant Enterobacteriaceae

新型抗菌辅助剂的鉴定和表征，以恢复对碳青霉烯类耐药肠杆菌科细菌的敏感性

• 批准号: 9754749
• 负责人: Kenneth Patrick Smith
• 金额: $ 5.72万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-27 至 2020-07-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9754749
• 关键词: Anti-Infective Agents; Antibiotic Resistance; Antibiotics; Antimicrobial Effect; Area; Bacteria; Biological Assay; Carbapenems; Cell Wall; Centers for Disease Control and Prevention (U.S.); Chemicals; Clinical; Collaborations; Collection; Consultations; Data; Doctor of Philosophy; Dose; Enterobacter; Enterobacteriaceae; Enzymes; Escherichia coli; Eukaryotic Cell; Goals; Growth; In Vitro; Infection; Klebsiella pneumonia bacterium; Knowledge; Laboratories; Libraries; Meropenem; Modeling; Moderate Activity; Modification; Multi-Drug Resistance; Mus; Organism; Pharmaceutical Chemistry; Pharmaceutical Preparations; Plasmids; Predisposition; Proteomics; Research; Resistance; Resolution; Resort; Structure; Structure-Activity Relationship; Testing; Therapeutic Trials; Thigh structure; Toxic effect; Work; alternative treatment; antimicrobial; base; beta-Lactams; carbapenem resistance; carbapenem-resistant Enterobacteriaceae; carbapenemase; cellular targeting; counterscreen; crosslink; effective therapy; efflux pump; enzyme activity; experimental study; high throughput screening; in vivo; insight; member; multi-drug resistant pathogen; mutant; novel; pathogen; response; scaffold; screening; synergism

Project Summary Antibiotic resistance in bacteria is compromising our ability to treat infection. Of alarming concern is emerging carbapenem resistance amongst members of the Enterobacteriaceae (so called carbapenem-resistant Enterobacteriaceae or CRE) such as Klebsiella pneumoniae and Enterobacter spp. Heretofore, carbapenems were the class of antibiotics of last resort against multidrug-resistant pathogens. Acquisition of broadly acting enzymes that destroy these drugs has made treatment of CRE problematic at best. Alternative treatments are either absent or highly toxic. Accordingly, the CDC has classified CRE as an urgent threat. There is pressing need for novel antimicrobials and new antimicrobial target identification. Importantly, bacteria containing the same functional carbapenemase enzymes show marked differences in susceptibility to carbapenems, suggesting that carbapenem resistance is multi-factorial. In fact, some strains remain clinically susceptible both in vitro and in vivo. We therefore hypothesize that novel adjunctive antimicrobials can be found that modulate factors contributing to resistance and thereby restore the efficacy of carbapenems in non-susceptible strains. Therefore, this proposal will use a comprehensive, high-throughput screening (HTS) assay to identify novel compounds that either directly inhibit CRE and/or render CRE susceptible to carbapenems. Following identification, we aim to characterize the mechanism of action of these novel compounds and gain insight into mechanisms of carbapenem resistance and CRE antimicrobial effect. The long-term goal is to use this knowledge to develop novel effective therapies for CRE.

项目总结

项目成果

Large-scale, in-house production of viral transport media to support SARS-CoV-2 PCR testing in a multi-hospital healthcare network during the COVID-19 pandemic.

大规模、内部生产病毒传输介质，以支持 COVID-19 大流行期间多医院医疗保健网络中的 SARS-CoV-2 PCR 检测。

• DOI: 10.1101/2020.04.29.20085514
• 发表时间: 2020
• 期刊: medRxiv : the preprint server for health sciences
• 作者: Smith,KennethP;Cheng,Annie;Chopelas,Amber;DuBois-Coyne,Sarah;Mezghani,Ikram;Rodriguez,Shade;Talay,Mustafa;Kirby,JamesE
• 通讯作者: Kirby,JamesE

The Inoculum Effect in the Era of Multidrug Resistance: Minor Differences in Inoculum Have Dramatic Effect on MIC Determination.

• DOI: 10.1128/aac.00433-18
• 发表时间: 2018-08-01
• 期刊: Antimicrobial agents and chemotherapy
• 影响因子: 4.9
• 作者: Smith, Kenneth P;Kirby, James E
• 通讯作者: Kirby, James E

The Limit of Detection Matters: The Case for Benchmarking Severe Acute Respiratory Syndrome Coronavirus 2 Testing.

• DOI: 10.1093/cid/ciaa1382
• 发表时间: 2021-11-02
• 期刊: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
• 作者: Arnaout R;Lee RA;Lee GR;Callahan C;Cheng A;Yen CF;Smith KP;Arora R;Kirby JE
• 通讯作者: Kirby JE

Image analysis and artificial intelligence in infectious disease diagnostics.

• DOI: 10.1016/j.cmi.2020.03.012
• 发表时间: 2020-10
• 期刊: Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases
• 作者: Smith KP;Kirby JE
• 通讯作者: Kirby JE

The convergent total synthesis and antibacterial profile of the natural product streptothricin F.

• DOI: 10.1039/d1sc06445b
• 发表时间: 2022-03-24
• 期刊: Chemical science
• 影响因子: 8.4
• 作者: Dowgiallo MG;Miller BC;Kassu M;Smith KP;Fetigan AD;Guo JJ;Kirby JE;Manetsch R
• 通讯作者: Manetsch R