Mycobacterium tuberculosis (Mtb), the etiologic agent of tuberculosis (TB), causes more deaths worldwide than any single infectious agent. The rifamycin-based standard-of-care (SOC) regimen is efficacious but requires 6 months of treatment, making it difficult to implement globally. Although high-dose rifamycin regimens that may shorten treatment to 4 months are currently being trialed, neither these regimens nor the SOC will benefit patients with rifamycin-resistant or multidrug-resistant (MDR-) TB, of which approximately 600,000 new cases occurred in 2016. Current MDR-TB treatment regimens are toxic, require 9-24 months of administration and cure only about 50% of patients. The availability of new regimens containing 3 or more novel drug classes without pre-existing resistance could be transformational, especially if the treatment-shortening effects of rifamycins could be replaced. The overall objectives of the consortium are (i) to discover and develop novel TB drug candidates targeting various aspects of bacterial proteostasis (the capacity to coordinately synthesize and degrade proteins), and (ii) to combine these candidates into novel 3- or 4-drug regimens capable of shortening the treatment of drug-susceptible or RR-TB. Projects 1-3 will focus on the identification and advancement of preclinical candidates, each targeting a component of the proteostasis machinery ([1] ClpC1, [2] ClpP1P2 protease, [3] RNA polymerase). Using a combination of an in vitro pharmacodynamics system (hollow fiber model) and 3 complementary murine TB models (?standard? BALB/c mice, C3H3B/FeJ mice with more human- like caseous [necrotic] lung lesions, immunocompromised nude mice), Project 4, which is described in this application, will (1) characterize the exposure-response relationships that govern bactericidal activity, resistance suppression and, in the case of TBI-223, toxicity of lead compounds emerging from Projects 1-3 plus TBI-223, the TB-focused oxazolidinone, which is already a pre-clinical candidate sponsored by TB Alliance, (2) evaluate the impact of caseating lung lesions on these exposure-response relationships, and (3) develop the most effective drug combinations containing the optimal doses of pre-clinical candidates emerging from Projects 1-4 and evaluate their treatment-shortening potential relative to the SOC in predictive murine models. The overarching goal is to develop one or more pharmacodynamically-optimized, universally active, treatment-shortening regimens targeting Mtb proteostasis. Because this effort will occur in the context of a robust, highly collaborative TB drug development program sponsored by TB Alliance pre-clinical candidates emerging from Projects 1-4 may also be combined with other promising pre-clinical leads/candidates and clinical candidates that target mechanisms other than proteostasis, thus amplifying the potential opportunities for discovery of transformational regimens.
