The growing threat of antibiotic resistant microorganisms has prompted a search for new drug targets as well as for a better understanding of mechanisms of resistance in order to design effective inhibitors to combat antibiotic resistance and reduce the further spread of resistant bacteria. This application centers on the recently discovered kinases FomA and FomB that represent a novel mechanism of resistance to the widely used antibiotic fosfomycin. These two novel proteins inactivate fosfomycin through phosphorylation. In contrast to all previously known fosfomycin resistance proteins (FosA, FosB and FosX type) the FomA and FomB proteins do not belong to the vicinal chelate superfamily of enzymes, but are members of the superfamily of kinases. They show low sequence identity (~25% at the most) to any known proteins and no sequence identity to the previously described fosfomycin resistance proteins of FosA, FosB or FosX type. In addition, the phosphorylation and diphosphorylation of the phosphonate function has proven to be reversible. The structural studies will characterize the molecular fold of these two unusual kinases and provide a basis for understanding the mechanism of resistance by phosphorylation. Such knowledge will guide the design of inhibitors that will be effective against antibiotic resistance.

Public Health Relevance

The basis of the proposal is crystal structure determination of two novel kinases FomA and FomB that confer high-level resistance to common antibiotic fosfomycin. The goal of the proposal is to understand the mechanism of fosfomycin inactivation in order to design inhibitors that will be effective against antibiotic resistance. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Research Grants (R03)
Project #
1R03AI074770-01A1
Application #
7469704
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Perdue, Samuel S
Project Start
2008-07-24
Project End
2010-06-30
Budget Start
2008-07-24
Budget End
2009-06-30
Support Year
1
Fiscal Year
2008
Total Cost
$73,500
Indirect Cost
Name
Louisiana State University A&M Col Baton Rouge
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
075050765
City
Baton Rouge
State
LA
Country
United States
Zip Code
70803
Pakhomova, Svetlana; Bartlett, Sue G; Doerner, Pamela A et al. (2011) Structural and biochemical insights into the mechanism of fosfomycin phosphorylation by fosfomycin resistance kinase FomA. Biochemistry 50:6909-19
Pakhomova, Svetlana; Bartlett, Sue G; Augustus, Alexandria et al. (2008) Crystal structure of fosfomycin resistance kinase FomA from Streptomyces wedmorensis. J Biol Chem 283:28518-26