A Novel Therapeutic Agent for the Treatment of Gram-positive Infections

一种治疗革兰氏阳性感染的新型治疗剂

• 批准号: 10078988
• 负责人: James Leif Smith
• 金额: $ 23.31万
• 依托单位: SANO CHEMICALS, INC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-13 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10078988
• 关键词: Address; Anabolism; Anti-Bacterial Agents; Antibiotics; Bacteria; Bacterial Infections; Biological; Biomedical Engineering; Bioreactors; Carbon; Cell Density; Centers for Disease Control and Prevention (U.S.); Cessation of life; Child; Clinical; Community Healthcare; Coupled; Culture Media; DNA sequencing; Development; Dose; Drug Kinetics; Drug resistance; Elderly; Engineering; Ethyl Methanesulfonate; Fermentation; Financial Hardship; Gene Cluster; Genetic; Genomics; Goals; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Growth; Healthcare Systems; Human; In Vitro; Incidence; Individual; Infection; Intravenous; Investigation; Investigational Drugs; Investigational New Drug Application; Kidney; Knowledge; Lead; Liver; Measures; Methods; Molecular; Morbidity - disease rate; Multiple Bacterial Drug Resistance; Mus; Mutagenesis; Mutation; Natural Products; Nitrogen; Oxygen; Patients; Peptides; Performance; Pharmaceutical Preparations; Predisposition; Production; Regulatory Element; Research; Resistance; Ribosomes; Sepsis; Serum; Sodium Chloride; Source; Staphylococcus aureus; Staphylococcus aureus infection; Streptococcus mutans; Streptococcus pneumoniae; System; Systemic infection; Techniques; Temperature; Therapeutic Agents; Time; Toxic effect; United States; Vancomycin; Work; acute infection; analog; antimicrobial; bactericide; base; distilled alcoholic beverage; experience; experimental study; genetic manipulation; genomic locus; improved; in vivo; methicillin resistant Staphylococcus aureus; mortality; mutant; next generation; novel; novel therapeutics; pathogen; peptide analog; preclinical development; preclinical study; promoter

Project Summary The work described in the application is necessary for furthering the development of a new therapeutic for treating Gram-positive infections. Preliminary in vitro and in vivo activity studies of novel analogs of mutacin 1140 suggest that they hold great promise as an antimicrobial product for clinical use. Mutacin 1140 is produced by the bacterium Streptococcus mutans JH1140 and the bacterium has been engineered to synthesize novel analogs of the native compound. Our studies have revealed that select mutacin 1140 analogs have a rapid bactericidal activity and that they are superior to native compound in terms of inhibitory activity, serum stability, and performance in an in vivo infection study. Further, the analogs have been shown to be more effective than vancomycin in treating a systemic MRSA infection. Mutacin 1140 analogs have no observable toxicity in mice at a 50 mg/kg intravenous dose. Furthermore, the analogs were shown to significantly reduce bacterial load of MRSA in the kidneys and liver of infected mice in an acute infection study. All these studies point to the need to further the preclinical development of one or more of the novel analogs of mutacin 1140. The major impediment to furthering investigational studies on these unique antibacterial compounds is the poor yield from culture liquor. The goal of this application is to enhance the yield and purity of mutacin analogs following fermentation. Three approaches will be explored to increase the yield of the antibacterial compound. First, media components will be screened to determine their effect on the production levels of the antibacterial compound. Second, a molecular based approach will be used to determine whether an increase in production of the analogs is possible through genetic manipulation of S. mutans. Our third approach is transposon or ethyl-methanesulfonate (EMS) random mutagenesis coupled with next-generation DNA sequencing to identify mutations that lead to enhanced production. The last component of the application is to determine the most effective means of extracting and purifying the antibacterial compound from the fermentation liquor. These experiments will enable exploratory studies for defining a novel drug product for investigational new drug (IND) studies.

项目总结

项目成果

Drug discovery through the isolation of natural products from Burkholderia.

• DOI: 10.1080/17460441.2021.1877655
• 发表时间: 2021-07
• 期刊: EXPERT OPINION ON DRUG DISCOVERY
• 影响因子: 6.3
• 作者: Foxfire, Adam;Buhrow, Andrew Riley;Orugunty, Ravi S.;Smith, Leif
• 通讯作者: Smith, Leif

Evaluation of analogs of mutacin 1140 in systemic and cutaneous methicillin-resistant Staphylococcus aureus infection models in mice.

• DOI: 10.3389/fmicb.2022.1067410
• 发表时间: 2022
• 期刊: FRONTIERS IN MICROBIOLOGY
• 影响因子: 5.2
• 作者: Ju, Min;Joseph, Thushinari;Hansanant, Nopakorn;Geng, Mengxin;Williams, McKinley;Cothrell, Andrew;Buhrow, Andrew Riley;Austin, Frank;Smith, Leif
• 通讯作者: Smith, Leif