Discovering new therapeutic strategies for tuberculous meningitis

There are opportunities to improve tuberculous meningitis (TBM) treatment, reducing its 30% case-fatality. A resurgent pipeline of new anti-tuberculosis drugs may kill bacteria faster than current drugs, and targeted anti-inflammatory drugs may control life-threatening brain inflammation better than standard-of-care corticosteroids. However, the opportunities are impaired by poor understanding of disease and therapeutic mechanisms; a lack of animal models that predict likely efficacy of new drugs/regimens in humans; and no biomarkers of successful treatment outcomes. We will therefore create a platform for the pre-clinical/clinical discovery and development of new therapeutic strategies for TBM, linking human experimental medicine in Vietnam and South Africa with animal models. We will study two potent bedaquiline-containing anti-TB regimens and two TNF-targeted anti-inflammatory drugs in humans and mice with TBM. We aim to quantify the relationship between anti-tuberculosis drug concentrations, bacterial killing, inflammation, and outcome; define the mouse model’s ability to recapitulate human therapeutic relationships; and discover novel inflammatory and physiological biomarkers of outcome. We will also study the therapeutic potential of three new drugs for TBM (ganfeborole; telecebec; TBAJ-876) in the rabbit and mouse TBM models, establishing their role in the discovery and development of new therapeutic strategies for TBM. Key words: tuberculous meningitis; therapeutic strategies