! Antibiotics that inhibit cell wall synthesis serve as an important strategy to control bacterial pathogens. These molecules prevent expansion of the peptidoglycan sacculus, resulting in the accumulation of cellular contents without associated growth, ultimately leading to cellular lysis. Recently it has been reported that some Gram- positive bacteria respond to cell wall-active antibiotics by stimulating the production of the nucleotide second messenger (p)ppGpp. Since this molecule can inhibit many cellular processes, (p)ppGpp synthesis in antibiotic treated cells reduces overall biosynthesis and thereby potentially lessen the potentially lethal incompatibility of continued accumulation of cellular content and inhibited cell growth. This proposal is aimed at understanding several aspects of this mechanism. First, how does (p)ppGpp specifically act to inhibit cytoplasmic biosynthesis in response to cell wall active antibiotics? And second, how are cell-wall active antibiotics detected ? what is the signal transduction cascade leading to the activation of (p)ppGpp synthesis? Finally, if this homeostatic mechanism facilitates survival in the presence of cell wall-active antibiotics, interference with this mechanism should make the bacteria more sensitive to these compounds. We will therefore use insights gained in investigating these questions to identify molecules that interfere with this mechanism and determine if they alter the sensitivity of the bacteria to cell wall-active antibiotics. !

Public Health Relevance

Antibiotics serve as the basic strategy to control bacteria that cause disease. However, many disease-causing bacteria sense the presence of antibiotics and change in order to become less sensitive. This proposal aims to understand how this happens with the ultimate goal of identifying inhibitory molecules that target this process and thereby increase the sensitivity of bacteria to pre-existing antibiotics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI135427-01
Application #
9434559
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Ernst, Nancy L
Project Start
2018-06-01
Project End
2020-05-31
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032