New classes of drugs are needed to treat tuberculosis (TB) in order to combat the emergence of resistance to existing agents and shorten the duration of therapy. A series of novel bioreductively-activated benzotriazine oxide compounds have been identified and shown to be potently bactericidal against both replicating and nonreplicating M. tuberculoisis (Mtb) bacilli. The lead compound from the series has excellent solubility, permeability and oral bioavailability, making it an excellent candidate for further optimization. The lead compounds have also been demonstrated to be rapidly bactericidal, have low frequency of resistance and are not antagonistic to the two frontline TB antibiotics, isoniazid (INH) and rifampin (RIF). This four year program will serve to optimize this series of compounds with the overall goal of identifying a preclinical development candidate. Additional analogs of our lead compound will be produced using parallel synthesis techniques and traditional medicinal chemistry approaches. These compounds will first be assayed for in vitro activity against replicating and non-replicating Mtb, followed by a counterscreen for cytotoxicity. Active compounds will be assessed for solubility, permeability, and metabolic stability to select compounds for pharmacokinetic (PK) studies in mice. At this stage candidates will also be evaluated for activity against drug-resistant strains, synergy/antagonism with INH and RIF and frequencies of resistance. Candidates with favorable parameters in all of these assays will then be evaluated in mouse efficacy models to determine the minimum effective doses (MED) and minimum bactericidal dose (MBD). Promising compounds will be ranked by their minimal effective dose (MED) and minimal bactericidal dose (MBD) values in order to select an optimized preclinical candidate. The top candidate will additionally be evaluated in a drug combination study, a pharmacodynamic (PD) parameter study and in the paucibacillary mouse model of latent TB infection.
The goal of the project is to create improved treatment regimens for XDR/MDR-TB infections that will be shorter and have fewer side effects. The development of a shorter, more effective treatment regimen will increase patient compliance and therefore slow down the emergence of drug resistance and protect vulnerable populations not only in the United States but worldwide.
| Chopra, Sidharth; Matsuyama, Karen; Tran, Tran et al. (2012) Evaluation of gyrase B as a drug target in Mycobacterium tuberculosis. J Antimicrob Chemother 67:415-21 |
| Chopra, Sidharth; Koolpe, Gary A; Tambo-Ong, Arlyn A et al. (2012) Discovery and optimization of benzotriazine di-N-oxides targeting replicating and nonreplicating Mycobacterium tuberculosis. J Med Chem 55:6047-60 |
