# Preclinical modeling to study Tuberculous Meningitis

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $810,795

## Abstract

Tuberculous (TB) meningitis is a serious, life-threatening disease affecting vulnerable populations including
HIV-infected individuals and young children. Early diagnosis is challenging and outcomes are poor even with
prolonged antimicrobial treatment (≥12 months). Although several key antimicrobials have limited central
nervous system (CNS) penetration and immunopathology is the major driver of neurological damage,
pulmonary TB is still used as the treatment paradigm, with limited efforts to utilize preclinical models of TB
meningitis to optimize treatment.
 We have developed a rabbit model of TB meningitis that replicates key neuropathological features of
human disease. Additionally, we have developed several novel, clinically translatable positron emission
tomography (PET) tracers to perform holistic, unbiased and noninvasive measurements of pathophysiological
processes in live animals. These include 124I-DPA-713 for cerebral inflammation, 11C-rifampin, 76Br-bedaquiline
and 18F-linezolid to measure antimicrobial penetration into the CNS, benzothiazinone (BTZ) analogs to directly
detect Mycobacterium tuberculosis and 18F-albumin / 11C-verapamil to study blood-brain barrier (BBB)
permeability / drug efflux transporter activity respectively. Given the importance of rifampin for the treatment of
TB meningitis, we performed detailed pharmacokinetic (PK) studies using dynamic 11C-rifampin PET in rabbits
and humans (Tucker et al. Sci Transl Med 2018). We demonstrate that rifampin penetration (area under the
curve) into infected-brain lesions is limited, spatially heterogeneous and substantially decreases within two
weeks of starting treatment (32% to 11%). Importantly, rifampin concentrations in cerebrospinal fluid (CSF) do
not correlate well with those in infected-brain lesions. First-in-human 11C-rifampin PET in a TB meningitis
patient was safe, well tolerated and demonstrated similar limited and heterogeneous rifampin penetration.
 We will utilize these novel imaging tools in the rabbit model to provide mechanistic insights into TB
meningitis and key information to optimize treatments: a) measure the penetration of novel TB drugs, including
those active against multi-drug resistant TB, into infected-brain lesions as well as provide insights into the
relevance of discordant CSF and brain tissue levels; b) compare linezolid and high-dose rifampin based
regimens and elucidate the role of BBB permeability and efflux transporters in drug exposures in the CNS; c)
perform longitudinal multi-modality imaging to simultaneously visualize intralesional bacterial burden,
inflammation and antimicrobial exposure during TB treatments in live animals to correlate the effect of
intracerebral inflammatory responses and antimicrobial exposures with the treatment outcome. These
assessments are not feasible with current technologies that require resected tissues. This proposal fulfills an
important gap in TB drug development and treatment optimization for a devastatin...

## Key facts

- **NIH application ID:** 10129272
- **Project number:** 5R01AI145435-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Sanjay K Jain
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $810,795
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129272

## Citation

> US National Institutes of Health, RePORTER application 10129272, Preclinical modeling to study Tuberculous Meningitis (5R01AI145435-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10129272. Licensed CC0.

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