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Preclinical development of Novo29, a new antibiotic

Preclinical development of Novo29, a new antibiotic
新型抗生素Novo29的临床前开发
批准号:
9914205
负责人:
Losee Lucy Ling
金额:
$98.74万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-01-10 至 2022-03-31

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项目成果

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中文摘要
翻译
这个项目的目标是继续开发我们的新型抗菌剂Novo29,使其成为一种治疗药物
英文摘要
The goal of this program is to continue developing our novel antimicrobial, Novo29, into a therapeutic for treating a wide range of infections caused by Gram-positive pathogens including Staphylococcus aureus, Streptococcus pneumoniae, and Bacillus anthracis. Using our iChip culturing technology, NovoBiotic has been exploiting previously uncultivable bacteria that make up 99% of all environmental microorganisms for production of new antibiotics. In 2015, NovoBiotic reported the discovery of teixobactin, the first member of a novel class of peptidoglycan synthesis inhibitors. We have since discovered Novo29, yet another promising and potent inhibitor of Gram-positive pathogens. Like teixobactin, Novo29 rapidly kills bacteria by inhibiting bacterial cell wall synthesis. However, Novo29 is significantly smaller than teixobactin, shows different target binding characteristics, and does not have serum gelation issues that require special formulations. Novo29 showed excellent efficacy against MRSA in two mouse models of infection (septicemia and thigh infection). The compound showed promising pharmacokinetic properties in mice, and is metabolically stable when incubated with liver microsomes. No spontaneous resistance (<10-10) occurred against S. aureus, and serial passaging in sublethal concentrations of drug failed to generate resistance. All these results demonstrate promising potential for Novo29 to treat drug-resistant infections. The goal of this project is to continue advancing Novo29 through preclinical research in preparation for IND-enabling studies. This work will include: (Aim 1) produce enough compound through fermentation to conduct all proposed studies in this grant, and for IND-enabling studies; (Aim 2) establish expanded MIC90s for pathogens isolated from recent clinical infections. Determine MBCs, time-kill profiles and post antibiotic effect (PAE) against relevant pathogens; (Aim 3) continue evaluating toxicity and pharmacokinetic (PK) profiles in animal models. Identify and characterize any major microsomal metabolites. Evaluate drug-drug interactions, genotoxicity, and cardiac safety in in vitro assays. Determine which PK/PD parameter(s) best correlate with efficacy; (Aim 4) examine efficacy of Novo29 in animal models of pulmonary infection with MRSA and anthrax; (Aim 5) explore the structure activity relationship (SAR) of Novo29 through medicinal chemistry. Design and test back-up analogs that may have increased potency and oral bioavailability. At the conclusion of this grant, Novo29 will be prepared to enter formal IND-enabling studies and advance to the clinic.
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UV-Based Approach for Accessing New Antibiotics
  • 批准号:
    8469820
  • 项目类别:
  • 资助金额:
    $30.0万
  • 财政年份:
    2012
  • 负责人:
    Losee Lucy Ling
  • 依托单位:
UV-Based Approach for Accessing New Antibiotics
  • 批准号:
    8314495
  • 项目类别:
  • 资助金额:
    $30.0万
  • 财政年份:
    2012
  • 负责人:
    Losee Lucy Ling
  • 依托单位:
Isolating novel actinomycetes for antibiotic discovery
  • 批准号:
    7480833
  • 项目类别:
  • 资助金额:
    $29.9万
  • 财政年份:
    2008
  • 负责人:
    Losee Lucy Ling
  • 依托单位:
Isolating novel actinomycetes for antibiotic discovery
  • 批准号:
    8049200
  • 项目类别:
  • 资助金额:
    $99.96万
  • 财政年份:
    2008
  • 负责人:
    Losee Lucy Ling
  • 依托单位:
海外基金