The ability of some bacteria to survive antibiotic treatment is a serious problem for the treatment of infectious diseases. This is especially true fo the pathogen Mycobacterium tuberculosis (Mtb), the causative agent of human tuberculosis (TB). Global TB mortality rates are increasing, despite the aggressive and lengthy antibiotic chemotherapy used to treat the disease. One of the reasons for failed treatment is that even in drug susceptible disease a considerable population of bacteria can survive antibiotic therapy. I intend to study this phenomenon of phenotypic tolerance, often referred to as persistence, in mycobacteria. Phenotypic tolerance is poorly understood and difficult to study since it requires looking at individual cells rather than populations. Here, I propose a novel method based on fluorescent biosensors and time-lapse microscopy to test my hypothesis that bacterial physiological state predetermines antibiotic susceptibility on a single-cell level and that this stte can fluctuate in response to endogenous and exogenous stimuli. The results will give insight into the mechanisms underlying phenotypic tolerance in mycobacteria, leading to future work that will focus on developing new strategies for treating TB infections more rapidly.

Public Health Relevance

Global tuberculosis (TB) mortality rates are increasing, despite the aggressive and lengthy antibiotic chemotherapy used to treat the disease. One of the reasons for failed treatment is that even in drug susceptible disease a considerable population of bacteria can survive antibiotic therapy. The experiments proposed here are designed to identify and characterize individual mycobacterial cells that can survive antibiotic treatment, with future work aimed at developing therapies to treat TB therapies more rapidly.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32AI104287-01A1
Application #
8645267
Study Section
Special Emphasis Panel (ZRG1-F13-C (20))
Program Officer
Jacobs, Gail G
Project Start
2014-07-09
Project End
Budget Start
2014-07-09
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
$53,282
Indirect Cost
Name
Harvard College
Department
Microbiology/Immun/Virology
Type
Schools of Public Health
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115