Novel QcrB Inhibitors for the Treatment of Tuberculosis

Abstract
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is the biggest killer among
infectious diseases. TB is also responsible for a quarter of all deaths associated with Antimicrobial
Resistance (AMR). It is projected that by 2050, 75 million people, or one person every 12 seconds,
will die due to AMR associated with TB. Long treatment times and increasing resistance to TB
drugs have created the need to find new compounds with shorter treatment times and novel
mechanisms of action. Triazolopyrimidine (TZP) compounds may lead to treatment shortening
because they are effective against both replicating and non-replicating Mtb, and may address
drug resistance because they target QcrB (ubiquinone cytochrome C oxidoreductase), a protein
not currently targeted with existing TB drugs. During Phase I, we propose to optimize the
physicochemical and ADME-PK properties of the TZP series and study the effects of this series
in combination with other respiratory inhibitors such as bedaquiline. We will identify compounds
with suitable potency, in vivo exposure, and tolerability. We will use an optimized compound to
demonstrate efficacy in an animal model of TB infection and we will determine the kill kinetics and
growth inhibition properties of the compounds alone and in combination with other respiratory
inhibitors under replicating and non-replicating conditions.
At the conclusion of these studies, we will have demonstrated feasibility that the TZP series, in
combination with other respiratory inhibitors, results in treatment shortening. We will have
completed a proof of concept animal study to demonstrate in vivo efficacy. During Phase II, we
will complete lead optimization, further characterize the biological activity, and expand in vivo
studies.Project Narrative
Tuberculosis (TB) infection results in more deaths than HIV and is the leading infectious disease killer
responsible for more than 1 million deaths each year. Treatment requires at least 6 months of therapy and drug
resistance is increasingly common, which necessitates the development of agents that kill faster through novel
targets. We will develop a triazolopyrimidine compound as a new TB therapy, which may lead to treatment
shortening by acting on both replicating and non-replicating bacteria, and has a novel mode of action, which
addresses drug resistance.