Transport across two membranes by AcrAB-TolC

AcrAB-TolC 跨两膜转运

基本信息

批准号：
10377970
负责人：
HELEN I ZGURSKAYA
金额：
$ 49.39万
依托单位：
UNIVERSITY OF OKLAHOMA
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-03-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10377970
关键词：
Acinetobacter baumannii Address Affect Antibiotic Resistance Antibiotics Area Bacteria Bacterial Infections Biochemical Cell Membrane Permeability Chemosensitization Chimeric Proteins Clinical Colistin Complex Development Escherichia coli Funding Goals Infection Kinetics Knowledge Libraries Membrane Membrane Fusion Molecular Molecular Conformation Multi-Drug Resistance Multidrug-resistant Acinetobacter Multiple Bacterial Drug Resistance Pathogenesis Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Proteins Pump Research Resistance Role Series Structure Structure-Activity Relationship Therapeutic Toxic effect Virulence Walkers antibiotic efflux base chronic infection clinical application clinical development design drug discovery efflux pump experimental study inhibitor insight models and simulation multidisciplinary novel periplasm preclinical study preservation resistance mechanism resistant strain response therapeutic target tool

项目摘要

Project Description Multidrug efflux pumps as exemplified by AcrAB-TolC from Escherichia coli are the major contributors to clinical antibiotic resistance in bacteria and to various adaptive responses during pathogenesis and chronic infections. During the previous funding period, we made major advances in two areas: 1) understanding the molecular mechanism of efflux pump assembly and the role of periplasmic membrane fusion proteins in multidrug efflux across two membranes; and 2) the development of a synergistic computational and empirical approach to discovering efflux pump inhibitors with novel mechanisms of action. We successfully applied these advances to discover inhibitors that act in a novel way, by interacting with AcrA and inhibiting the assembly of the AcrAB- TolC complex. These efflux pump inhibitors potentiate activities of multiple antibiotics in various bacteria. The major goal of the proposed research is to establish the molecular mechanisms of the new efflux pump inhibitors and to optimize these inhibitors for use in combination with specific antibiotics and against specific multidrug resistant bacteria. The underlying hypothesis is that the broad potentiation activity of the discovered inhibitors is caused by their unique mechanism that traps efflux pumps in a poorly assembled and leaky conformation. In the proposed approach, biochemical, structural and kinetic experiments will be used synergistically with advanced computations to characterize the mechanism of efflux pump inhibitors and to optimize inhibitors acting on efflux pumps of multidrug resistant Acinetobacter baumannii. To optimize inhibitors, we will apply what is to our knowledge the most comprehensive platform available. The platform utilizes a set of strains with variable efflux capacities and outer membrane permeability barriers and allows to establish structure-activity relationships separately for efflux avoidance, inhibition and permeation across the outer membrane. Successful completion of the proposed experiments will help design efflux pump inhibitors that would be effective even in the context of multiple pumps and mechanisms of antibiotic resistance.