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FLHA and CCRM as Potential Antimicrobial Drug Targets

Investigators
Kahng, Lyn
Institutions
Stanford University
Start date
1997
End date
2002
Objective

The broad objective of the proposed project is to study the mechanism of the Type III secretory pathway which is used for the export of bacterial flagellar proteins in both Gram negative and positive bacteria, as well as for secretion of virulence factors in an array of plant and animal pathogenes.

The general aim of this proposal is to understand the pathogenesis of infectious diseases caused by microbes in which motility and/or secretion of influence factors is important in causing disease. This would include, but not be limited to, infectious diarrheal diseases and diseases caused by Helicobacter pylori.

More information

While homologs of the export system components have been identified across diverse species, the mechanism of export has not yet been elucidated.

The Type III secretory pathway is a widespread aspect of bacterial pathogenesis which merits closer study in this era of antibiotic resistance and the resurgence of infectious disease. This pathway will be studied in Caulobater crescent us, which is unique among the well developed models for flagellar biogenesis in offering the opportunity to study the polarity and cell cycle dependence of this process.

This work will focus on a central component of the pathway, FlhA, which is likely to function in export substrate recognition.

Specific Aims:

  1. To understand how FlhA functions in the organism, I will a) determine the temporal expression and subcellular localization of FlhA; b) utilize a genetic approach to define important functional determinants of the FlhA protein.
  2. To develop an assay of export function in order to assess altered export phenotypes.
  3. To identify other pathway components as well as novel proteins which interact with FlhA.
  4. To perform heterologous complementation studies using FlhA homologs from other species, thus identifying determinants important for general secretory function as well as those unique to a given genus or substrate class.
  5. To determine whether other genes are present in an operon with flhA and determine the physiological significance of their products.

The general aim of this proposal is to understand the pathogenesis of infectious diseases caused by microbes in which motility and/or secretion of influence factors is important in causing disease. This would include, but not be limited to, infectious diarrheal diseases and diseases caused by Helicobacter pylori.

Given that many enteric bacteria possessing Type III secretory pathways are often implicated in nosocomial infections, where drug resistance is widespread, we expect that understanding the molecular mechanism of this pathway will also lead to the development of novel antimicrobial therapies.

Funding Source
Nat'l. Inst. of Allergy and Infectious Diseases
Project number
5K08AI001510-04
Categories
Antimicrobial Resistance
Bacterial Pathogens