DNA GYRASE AND QUINOLONE RESISTANCE IN TUBERCULOSIS

Project Details

Description

DNA gyrase of Mycobacterium tuberculosis will be studied to better
understand acquisition of antibiotic resistance and factors that determine
intracellular DNA structure in mycobacteria. The two gyrase genes of M.
tuberculosis will be cloned, and their nucleotide sequences will be
determined to provide molecular information needed for analysis of
fluoroquinolone resistance. Then the gyrase genes from fluoroquinolone-
resistant clinical strains will be examined for mutations that will
account for resistance. Gyrase genes cloned from these strains will be
used to express gyrase, which will then be purified and studied in vitro
for resistance properties. To determine whether gyrase is required for
resistance, genetic complementation will be carried out using cloned,
wild-type gyrase genes introduced into quinolone-resistant clinical
strains. Inhibition of DNA synthesis in permeabilized cells will be
examined to identify strains in which resistance is due to non-gyrase
determinants. Gyrase inhibitors will also be used to obtain additional
mutants that have altered steady-state levels of supercoiling. These will
be used to ask whether perturbation of supercoiling interferes with
virulence by examining the ability of mutants to inhibit mycobacterial
survival and reproduction in cultured macrophages. Information obtained
from this program will define quinolone resistance in M. tuberculosis and
will begin to describe relationships between DNA supercoiling and
virulence in M. tuberculosis. The work is expected to help guide efforts
to develop new, more effective anti-tuberculosis agents.
StatusFinished
Effective start/end date9/30/9312/31/08

Funding

  • National Institute of Allergy and Infectious Diseases
  • National Institute of Allergy and Infectious Diseases
  • National Institute of Allergy and Infectious Diseases: $644,089.00
  • National Institute of Allergy and Infectious Diseases
  • National Institute of Allergy and Infectious Diseases: $560,178.00
  • National Institute of Allergy and Infectious Diseases: $551,403.00
  • National Institute of Allergy and Infectious Diseases
  • National Institute of Allergy and Infectious Diseases: $644,419.00
  • National Institute of Allergy and Infectious Diseases
  • National Institute of Allergy and Infectious Diseases
  • National Institute of Allergy and Infectious Diseases
  • National Institute of Allergy and Infectious Diseases
  • National Institute of Allergy and Infectious Diseases: $640,706.00
  • National Institute of Allergy and Infectious Diseases: $217,323.00
  • National Institute of Allergy and Infectious Diseases: $542,882.00
  • National Institute of Allergy and Infectious Diseases: $544,245.00

ASJC

  • Medicine(all)
  • Immunology and Microbiology(all)
  • Infectious Diseases
  • Genetics
  • Pulmonary and Respiratory Medicine
  • Microbiology

Fingerprint

Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.