The goal of this proposal is to characterize the mechanisms of allostery and drug recognition within the small multidrug resistance (SMR) protein family. Multidrug resistance (MDR) to antibiotics is the ability of bacteria to confer simultaneous resistance to a wide variety of chemically distinct molecules. While several new antibiotics exhibiting different chemical scaffolds have been successfully developed and modified, MDR remains a pervasive problem in hospitals and clinics. We will reveal the allosteric control mechanism and molecular interactions at the atomic level that enable SMR proteins to recognize a wide variety of drugs. These molecular motors require energy dependent conformational transitions and protein-protein macromolecular assemblies to carry out function. Our high-resolution structural biology approach will employ NMR spectroscopy to reveal the details at the molecular level. While biochemical and biophysical studies have laid the foundation for this research, the molecular mechanism by which these proteins recognize drugs, become activated, and subsequently confer resistance is unknown. Our studies will provide a structural dynamics-function correlation for providing insight into this significant human health problem, and in doing so will reveal a molecular picture of the MDR phenomenon from the standpoint of the SMR family that can be applied to other families in order to better understand clinical resistance.

Public Health Relevance

The impact of this research project will be to understand the underlying reasons for why multidrug resistance is manifested in hospitals and clinics. While there are many mechanisms for resistance, we will investigate the role of efflux proteins that reduce drug toxicity within the cell and therefore confer resistance to the host organism. Our study will be essential for defining the molecular traits of drugs necessary to inhibit efflux pumps.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01AI108889-01A1
Application #
8761801
Study Section
Macromolecular Structure and Function C Study Section (MSFC)
Program Officer
Korpela, Jukka K
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
New York University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10012