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Rockville, MD, United States

Nikonenko B.V.,Sequella | Apt A.S.,Central Research Institute for Tuberculosis
Tuberculosis | Year: 2013

Mice as a species are susceptible to tuberculosis infection while mouse inbred strains present wide spectrum of susceptibility/resistance to this infection. However, non-tuberculosis Mycobacterial infections usually cannot be modeled in mice of common inbred strains. Introduction of specific properties, such as gene mutations, recombinants, targeted gene knockouts significantly extended the use of mice to mimic human Mycobacterial infections, including non-tuberculosis ones. This review describes the available mouse models of tuberculosis and non-tuberculosis infections and drug therapy in these models. Mouse models of non-tuberculosis infections are significantly less developed than tuberculosis models, hampering the development of therapies. © 2013 Elsevier Ltd. All rights reserved. Source


Grant
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 587.86K | Year: 2011

DESCRIPTION (provided by applicant): Tuberculosis (TB) has a massive impact on global health. The World Health Organization estimates that one- third of all people worldwide harbor latent TB infections, with sixteen million cases of active disease and nearly two million deaths caused by Mycobacterium tuberculosis (MTB) each year. TB infections are heterogeneous, and current medicines do not work equally well on all MTB bacteria. Efforts to replenish the TB treatment arsenal lag far behind the growing need,particularly for patients with multi- (MDR) or extensively- (XDR) drug-resistant-TB. In bacteria, many critical responses to environmental cues are performed by protein pairs comprised of a sensor kinase that auto-phosphorylates on a histidine and then transfers this phosphate to an aspartate on its cognate response regulator protein. The MTB histidine-aspartate phosphorelay systems are potentially attractive drug targets for two major reasons: First, of the two-component systems in MTB, at least one, MtrAB, is essential for viability even in rich media while others play key roles in virulence or persistence in vivo. Second, the high conservation among phosphoacceptor sites on the response regulators, and the absence of such proteins in mammals, suggest that developing pan-specific and non-toxic inhibitors may be possible. Our strategy is to focus here on the one essential 2CR of MTB, MtrAB, and target the signaling to the response regulator rather than within the kinase, overcoming problems encountered in approaches with 2CRs of other bacteria. In addition to target validation, our work is anticipated to produce at least one chemical scaffold suitable for expansion into a preclinical lead compound. Future plans will expand the targets to the larger family of mycobacterial 2CR response regulators. Specifically in this proof-of-concept work we plan to: Specific Aim 1. Develop an assay for inhibitors of the essential MTB 2CR MtrAB, and format it for HTS. We plan to adapt an innovative in vitro phospho-transferassay, synthesize a panel of candidate reporter substrates, and evaluate them. One reporter substrate will be selected to conduct Specific Aim 2. Specific Aim 2. Execute an MtrAB phospho-transfer high-throughput screen (HTS). Using the selected synthetic reporter substrate we will conduct an HTS on a 100,000 compound library comprised of compounds obtained from both the Sequella collection and from McMaster University's HTS facility. An anticipated hit rate of ca 0.1 -0.2 % is anticipated, thus providing 100-200 novel structures for Specific Aim 3. 3. Prioritize and expand hit scaffolds from Specific Aim 2. We will select the most promising structures and run in vitro secondary screens. A limited medicinal chemistry expansion will then produce 2-3 distinct scaffolds suitable for pursuit in a subsequent research phase. PUBLIC HEALTH RELEVANCE: Tuberculosis (TB) has a massive impact on global health, and efforts to replenish the TB treatment arsenal lag far behind the growing need, particularly for patients with multi- (MDR) or extensively- (XDR) drug-resistant-TB. We have chosen a promising new drug target, and propose to develop a screening method to identify molecules with significant potential as new drug candidates for the treatment of TB, MDR-TB, and XDR-TB.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 565.34K | Year: 2012

DESCRIPTION (provided by applicant): World Health Organization (WHO) declared tuberculosis (TB) a global health emergency; a distinction never accorded another disease. Two billion people are infected with Mycobacterium tuberculosis (Mtb) worldwide, leading to over 9 million new TB cases each year and nearly 2 million deaths. A considerable obstacle to TB control is the emergence of drug-resistant disease. Multidrug-resistant strains of Mtb (resistant to at least isoniazid [INH] and rifampicin [RIF]) resultin 440,000 new cases of MDR-TB each year in 41 countries. Determination of drug resistance is not routinely made prior to the start of treatment in many low-to-middle income country settings, and inappropriate treatment with the 1st-line drugs can lead totreatment failure and additional resistance development. An entirely new regimen with a shorter treatment time and activity against both TB and MDR-TB would reduce this problem, providing appropriate therapy for the majority of TB cases. MDR-TB global spread focused attention on the critical need to develop new drugs, and new drug regimens, for TB, but especially for MDR-TB. SQ109 (in development by Sequella) and TMC207 (in development by Tibotec, a Johnson and Johnson company) are two clinical stage drugcandidates that are now or will shortly be in Phase 2 efficacy studies in humans. Both have potent activity against MDR-TB clinical strains in vitro. TMC207 and Pyrazinamide (PZA), an established 1st-line TB drug, are synergistic in vivo and demonstrate excellent efficacy in a combination treatment regimen in a mouse model of TB. However, at least one additional drug will be needed to transition this regimen to humans, since PZA does not prevent the development of drug resistance to TMC207. The combinationof SQ109 and TMC207 is also synergistic in vitro. We hypothesize that SQ109, with a completely novel mechanism of action, can be combined with TMC207+PZA to further improve treatment efficacy and reduce relapse. This proposal outlines an important researchprogram between 2 companies with interesting drugs in clinical development, neither registered for use in humans. The results of these studies will give both companies a better understanding of combination drug efficacy and may identify a regimen that could be evaluated in the clinic. We propose to evaluate interaction of SQ109 and TMC207 in animal models of TB, with and without PZA, to generate nonclinical data on the interaction of these 3 drugs. Specific Aim 1. Evaluate drug-drug interactions of proposed combination treatments. Specific Aim 2. Evaluate efficacy of combination treatment regimens with these drugs. Specific Aim 3. Evaluate relapse rate of mice for the most effective regimen(s) identified in Aim 2. PUBLIC HEALTH RELEVANCE: New drugsand drug regimens to treat multidrug-resistant tuberculosis (MDR-TB) are desperately needed. Two drugs currently in clinical trials, SQ109 and TMC207, have excellent activity against MDR-TB and appear to have enhanced properties when used in combination with each other and with Pyrazinamide (PZA), a drug currently used for TB treatment. In this application, we propose to further characterize this promising new drug combination, with the goal of obtaining the necessary information to allow us to move forward with clinical trials.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 594.66K | Year: 2009

DESCRIPTION (provided by applicant): Mycobacterium avium complex (MAC) and M. abscessus (MAB) are the two most common nontuberculous mycobacteria (NTM) that cause human disease, and the incidence of NTM infections has been increasing worldwide. Both the organisms are generally resistant to standard antimybacterial drugs and other antibiotics. Hence, there is an critical need for new antimicrobial agents to treat these infections. Capuramycins (CM) are a new class of nucleoside antibiotics that inhibit bacterial cell wall construction by blocking biosynthesis of peptidoglycan (PG). Because PG is unique to bacteria, antibiotics that inhibit its biosynthesis selectively target bacteria with less toxicity to the host. Even though PG is present in all bacteria, CM and analogues have a narrow spectrum of activity, with highest activity against Mycobacteria sp. We investigated several compounds in this class and identified SQ641 as the most active compound with excellent in vitro activity against M. tuberculosis and several NTM. Under this SBIR phase I research proposal, we intend to extend our in vitro studies with SQ641 to include more NTM strains and to investigate SQ641 activity against several different MAC and MAB strains in macrophages and appropriate animal models. These studies will determine whether SQ641 should advance to investigational new drug (IND)-directed preclinical studies in preparation for human clinical trials. PUBLIC HEALTH RELEVANCE: Mycobacterium avium complex (MAC) and M. abscessus (MAB) are the two most common nontuberculous mycobacteria (NTM) that cause human disease. Both are ubiquitous environmental organisms able to thrive in harsh conditions in soil or water. Both NTM can cause cavitary or nodular lung disease in individuals with preexisting lung conditions, or disseminated disease in HIV infected individuals with low blood CD4+ T-cell count (MAC) or infection of the soft tissues following trauma-inducing hospital procedures or cosmetic surgery (MAB). Infections with NTM are invariably acquired from environmental sources and are not contagious. Both MAC and MAB are generally resistant to standard anti-TB drugs and have variable susceptibility to second-line anti-TB drugs. Hence, the existing antimicrobial agents are inadequate to treat MAC and MAB infections and there is an immense need for new antimicrobial agents. Capuramycins (CM) are a new class of nucleoside antibiotics that inhibit bacterial cell wall by blocking biosynthesis of peptidoglycan (PG), a cell wall constituent unique to bacteria. Even though PG is present in all bacteria, CM are most effective against mycobacteria. We investigated several compounds in this antibiotic class and identified SQ641 as the most active, with excellent in vitro activity against a limited number of MAC and MAB strains. Under this SBIR phase I research proposal we intend to extend our in vitro studies with SQ641 to include more NTM strains and to investigate its activity against MAC and MAB in macrophages and appropriate animal models. These studies are essential to advance the drug for clinical evaluation in human NTM infections.


Reddy V.M.,Sequella | Einck L.,Sequella | Andries K.,Tibotec Pharmaceuticals Ltd. | Nacy C.A.,Sequella
Antimicrobial Agents and Chemotherapy | Year: 2010

The in vitro interactions of two new antitubercular drugs, SQ109 and TMC207, with each other and with rifampin (RIF) were evaluated. The combination of SQ109 with TMC207 (i) improved an already excellent TMC207 MIC for M. tuberculosis H37Rv by 4- to 8-fold, (ii) improved the rate of killing of bacteria over the rate of killing by each single drug, and (iii) enhanced the drug postantibiotic effect by 4 h. In no instance did we observe antagonistic activities with the combination of SQ109 and TMC207. Rifampin activates cytochrome P450 genes to reduce the area under the curve (AUC) for TMC207 in humans. The presence of RIF in three-drug combinations did not affect the synergistic activities of SQ109 and TMC207, and SQ109 also dramatically decreased the MIC of RIF. SQ109 was active by itself, and both its activity was improved by and it improved the in vitro activities of both RIF and TMC207. Copyright © 2010, American Society for Microbiology. All Rights Reserved. Source

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