Project 4

Bacterial mechanisms and host pharmacokinetic factors that determine  persistence in paucibacillary TB

Goal: To identify bacterial and host factors that determine Mtb persistence.

Questions addressed:

  • What is the role of persistent, metabolically diverse Mtb populations in treatment duration and relapse?
  • Which bacterial factors promote persistence, and which represent novel drug targets?
  • Which metabolic products antagonize persistence and which metabolic adjuvants can enhance it?
  • Does bacterial burden correlate with likelihood of developing active TB disease?

Specific aims:

  1. To identify persistence mechanisms relevant to human TB treatment.
  2. To determine whether Mtb strains with moderately increased (but drug-susceptible) minimum inhibitory concentrations (MIC) are more prone to relapse after treatment, and identify the underlying mechanism of these MIC differences.
  3. To examine the in vivo relevance of persistence mutants in the rabbit disease model and the effect of different anti-TB drug concentrations (kill rates).

Significance: Identifying the factors that promote and antagonize Mtb persistence has the potential to aid in the search for optimized treatment strategies that can provide the best kill kinetics during the paucibacilliary TB stage, ultimately leading to treatment shortening.