# Bacterial Mechanisms and Host Pharmacokinetic Factors that Determine Persistence

> **NIH NIH U19** · RBHS-NEW JERSEY MEDICAL SCHOOL · 2020 · $770,673

## Abstract

Project 4 will study the paucibacillary state that occurs during Tuberculosis (TB) treatment. TB must be 
treated for a minimum of six months to prevent relapses. Prolonged treatment places a huge burden on TB 
control programs and creates many opportunities for non-compliance, relapse and the emergence of drug 
resistance. Efforts to improve the speed and effectiveness of TB treatments are hampered by critical gaps in 
our understanding of the paucibacillary stage of TB. Achieving improved kill kinetics at this stage would 
enable greatly shortened and more successful treatment. Foremost among these unknowns are 1) the 
biology of a probably metabolically diverse population of Mycobacterium tuberculosis (Mtb) that can persist 
in the presence of drugs without being killed (persisters), yet have normal MICs; 2) the bacterial and host 
pharmacokinetic/pharmacodynamic determinants of bacterial burden during the paucibacillary stage of TB 
treatment; and 3) the relationship between these bacterial and host factors and clinical relapse. Our group 
has identified a novel set of Mtb mutants with altered persistence. We have also identified clinical Mtb strains 
that are more prone to relapse after TB treatment, and found that they may have a new persister phenotype 
related to altered gene expression and moderately higher MICs against TB drugs. We have also noted 
altered drug pharmacokinetics within TB lesions that can decrease drug delivery and interact with bacterial 
MIC to decrease bacterial killing. To find ways to more rapidly overcome persistence during TB treatment, 
we must first understand all the bacterial and host elements that contribute to it. In this project, we will 1) 
identify persistence mechanisms relevant to human TB treatment; 2) determine whether Mtb strains with 
moderately increased (but drug-susceptible) MICs are more prone to relapse after treatment, and identify the 
underlying mechanism of these MIC differences along with useful predictive biomarkers; 3) examine In vivo 
relevance of persistence mutants in rabbit disease model and effect of lesional PK/MIC ratios on lesion-centric 
efficacy (kill rates). A full understanding of these factors and how they interact to determine the fate of 
Mtb bacilli remaining in host tissues during treatment is critical to developing shorter therapies

## Key facts

- **NIH application ID:** 10004558
- **Project number:** 5U19AI111276-08
- **Recipient organization:** RBHS-NEW JERSEY MEDICAL SCHOOL
- **Principal Investigator:** David Alland
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $770,673
- **Award type:** 5
- **Project period:** 2014-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10004558

## Citation

> US National Institutes of Health, RePORTER application 10004558, Bacterial Mechanisms and Host Pharmacokinetic Factors that Determine Persistence (5U19AI111276-08). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10004558. Licensed CC0.

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