Heterocyclic Inhibitors of QcrB as Novel Drugs for Infections Caused by Nontuberculous Mycobacteria

Project Summary/Abstract Non-tuberculosis mycobacteria (NTM) are a diverse group of environmental bacteria and opportunistic pathogens capable of causing numerous human infections, the most common of which is NTM pulmonary disease (NTM-PD). The most clinically relevant pathogens causing NTM-PD are members of the Mycobacterium abscessus complex (Mab) and the Mycobacterium avium complex (MAC). NTM-PD is especially problematic in immunosuppressed patients or those with lung conditions such as cystic fibrosis or chronic obstructive pulmonary disease, dramatically worsening the prognosis of such patients. Many NTM, including Mab and MAC, are intrinsically resistant to antibiotics, making the treatment of NTM-PD exceptionally difficult. Currently recommended therapeutic courses require the administration of ≥3 antibiotics for at least 12- 18 months. This intensive treatment frequently leads to drug induced toxicity and the potential for adverse drug-drug interactions while resulting in NTM clearance in only 34-67% of cases caused by drug susceptible NTM and 11-21% of cases caused by drug resistant NTM, with rates of relapse or recurrence ranging from 25- 49% in “cured” individuals. Therefore, new and safe drugs, with novel mechanisms of action are desperately needed to effectively treat NTM-PD by reducing treatment time, preventing relapse/recurrence and improving clinical outcomes, with reduced drug-induced adverse events. Fimbrion is developing a small molecule series that targets the Mycobacterium tuberculosis (Mtb) respiratory protein QcrB. We have made substantial progress optimizing the drug-like properties of our QcrB inhibitors, which display low-nanomolar potency against Mtb, possess good drug-like properties, have excellent in vivo oral pharmacokinetic (PK) profiles (high oral bioavailability and low intrinsic clearance) and show little-to-no eukaryotic cytotoxicity (CC50), with typical safety indices (SI) CC50/IC50 >1000. As QcrB is conserved between Mtb and the NTMs, we tested 30 of our QcrBMtb inhibitors against representative strains of the Mab and MAC and identified several compounds with good anti-Mab activity (IC50 <1 µM), with our exemplar lead displaying IC50 = 77 nM. In Aim 1 of our SBIR Phase I, we will focus on curating a library of existing QcrB inhibitors and newly synthesized compounds, to screen for Mab activity. Compounds with activity will also be screened for solubility, metabolic stability, and cytotoxicity, with PK profiles acquired for select compounds. In Aim 2 we will examine the spectrum of activity (SoA) for 3-5 lead anti-Mab compounds against a panel of Mab isolates, as well as spot check for other anti- NTM activity. 2-3 of our most potent anti-Mab compounds, with the best PK profiles, will be assessed in vivo for oral efficacy against Mab in an acute NTM-PD mouse model, and the top compounds will be assayed for potential safety and drug-drug interaction liabilities. Success in this Phase I project will be defined as 1) identifying of compounds with in vitro potency against Mab and good pharmacokinetic properties, and 2) demonstrating proof of principle efficacy data in an NTM mouse model, with no identified safety liabilities.