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Membrane-active quinoline and quinazoline antibacterials that target Gram positive pathogens

针对革兰氏阳性病原体的膜活性喹啉和喹唑啉抗菌剂

基本信息

批准号：
10563142
负责人：
Ambrose Lin Yau Cheung
金额：
$ 79.94万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10563142
关键词：
Affinity Chromatography Animal Model Anti-Bacterial Agents Antibiotic Therapy Antibiotics Bacteria Binding Binding Proteins Biological Assay Cells Daptomycin Data Defect Derivation procedure Drug Kinetics Dyes Electron Microscopy Endocarditis Ensure Enterococcus Enterococcus faecalis Enterococcus faecium Evaluation Studies Exhibits Frequencies Genetic Genomics Goals Gram-Positive Bacteria Hospitals In Vitro Infection Infection Control Infectious Skin Diseases Infective endocarditis Lead Length of Stay Libraries Linezolid Lipid Bilayers Lipids Mass Spectrum Analysis Measures Medicine Membrane Microsomes Minnesota Modeling Modification Molecular Multi-Drug Resistance Mus Mutation New Agents Nosocomial Infections Organism Oryctolagus cuniculus Pathogenicity Pharmaceutical Preparations Plasma Proteins Positioning Attribute Procedures Property Proteomics Public Health Publishing Quinazolines Quinolones Research Resistance Safety Series Serum Solubility Specificity Staphylococcus aureus infection Staphylococcus epidermidis Streptococcus pneumoniae Structure Structure-Activity Relationship Toxic effect Universities Vancomycin Work activity-based protein profiling analog aqueous bactericide biochemical tools biophysical tools carbonyl group crosslink cytotoxicity design drug development drug discovery drug disposition efficacy evaluation efficacy study improved in vivo lipophilicity medical schools methicillin resistant Staphylococcus aureus mutant novel pathogen quinoline scaffold screening simulation

项目摘要

Abstract Infections due to resistant Gram+ organisms are on the rise, likely due to a variety of factors including longer hospital stay, increased frequency of invasive procedures and pervasive antibiotic therapy. Compounding the problem is the emergence of multi-drug resistance (MDR) among many Gram+ pathogens (MRSA, S. epidermidis, Enterococcus and S. pneumoniae). Despite antibiotic stewardship and infection control, new agents against these Gram+ pathogens are urgently needed. After screening a ~60,000 preselected compound library, we obtained DNAC-2, a 4-hydroxyquinoline derivative, that exhibited antibacterial activities against MRSA and Enterococcus. We subsequently synthesized 3 series of analogues involving over 50 compounds. Two of these analogues in the 2th series, JRS-3-56 (compound 1) and JRS-4-32 (compound 2), were cidal against MRSA, S. epidermidis, E. faecalis and E. faecium, with MIC ≤0.2 μg/ml. However, both 1 and 2 have poor predicted aqueous solubility with high cLogP (7.7 and 6.0, respectively). Conversion of quinoline to quinazoline for 1 improved the cLogP (from 6.06 to 5.08) but led to a slight increase in MIC (0.25 to 2 µg/ml). In the latest series, we introduced a carbonyl group at C-4 and a C to N substitution at the C-1 position, yielding compounds 3 and 4 with low cLogPs and very low MIC (0.06 µg/ml for USA300), accompanied by a much tighter SAR. Using macromolecular synthesis assays, membrane-specific dye FM4- 64 and electron microscopy studies, we have evidence that 1 and 2 target the Gram+ membrane (3 and 4 also resulted in membrane defect as detected by the FM4-64 dye), but not Gram- or eukaryotic membrane, thus implying some degree of specificity. However, the exact target of these compounds which likely differs from daptomycin, is not known. In this application, we seek to define the mechanism of action of these quinoline/quinolone derivatives and further explore the SAR that governs in vitro and in vivo activities and drug disposition properties. Accordingly, we have the following specific aims: 1) design and synthesize quinoline/quinolone derivates by defining the SAR that governs activity against major Gram+ pathogens and drug disposition properties (MIC, solubility, overt toxicity and serum binding etc.); 2) delineate the mechanism of action of the quinoline/quinolone derivatives with genetic, biochemical and biophysical tools; 3) pharmacokinetic and efficacy studies where candidates compounds will be evaluated for their drug disposition properties to ensure safety and selectivity followed by selection of “lead” compounds for full PK evaluation and efficacy studies with two animal models. The goal of these studies is to identify “druggable membrane-active compounds” with broad Gram+ activity. If successful, we believe these compounds will represent a new class of membrane-active compounds that offer a significant advance in drug development.

摘要