The overall objective of this project is to further develop a novel chemical class of tuberculosis (TB) therapeutic agents, the spectinamide series, for use against MDR and XDR strains of Mycobacterium tuberculosis (Mtb) and identify, through a series of in vitro and in vivo assays, a preclinical candidate. TB is a lethal infectious disease, second only to HIV/AIDS as a cause of death. Estimates by the World Health Organization show one-third of the world population is infected with Mtb, the bacterium that causes TB;approximately 10% of infected individuals will develop active TB at some time in their lives. Of recent concern is the rising number of TB cases involving strains that are multidrug-resistant (MDR), which is defined as being resistant to treatment with isoniazid and rifampicin, the two first-line antibiotics for TB therapy and those that are extensively drug-resistant tuberculosis [XDR TB;defined as being resistant to isoniazid and rifampicin (as for MDR TB) and also to any fluoroquinolone and at least one of the three injectable second-line drugs (i.e., amikacin, kanamycin, or capreomycin)]. Treatment options for MDR/XDR TB include the two remaining first- line agents, ethambutol and pyrazinamide, second-line agents to which the strain is not resistant, such as streptomycin, as well as unproven agents such as linezolid, amoxicillin/clavulanate, clarithromycin, clofazimine and imipenem. Research suggests that at least four drugs and 18-24 month duration of treatment may be required for successful therapy of XDR TB;however, toxicity of the agents may preclude patients from being effectively treated. There is a clear unmet medical need for efficacious and safe drugs to be used as treatment for MDR/XDR TB. The novel spectinomycin analogs outlined in this proposal possess potent in vitro activity against MDR/XDR TB (MIC 0.4-1.6 5g/mL), act via a bactericidal mechanism of action, have demonstrated ability to enter macrophages, the host location of TB infections, and are safe compounds, displaying low in vitro cytotoxicity and no observed in vivo toxicity. These overall characteristics advocate for the rapid development of these compounds as a safe alternative treatment for drug resistant TB. We will, in conjunction with our collaborators, Dr. Richard Lee and Helena Boshoff, characterize the in vitro properties of the spectinamide class, including potency against MDR/XDR TB isolates, minimum toxicity against mammalian cell lines and metabolic stability. We will, then scale-up the synthesis of the most favorable analogs for in vivo studies and optimize the synthetic chemistry route in the process. Finally, in collaboration with Dr. Anne Lenaerts, we will evaluate in vivo toxicology, pharmacokinetics and efficacy in mice. These experiments will allow us to identify a final lead and backup compound suitable for advancement to Phase II. In Phase II, we will conduct long term in vivo efficacy studies of the preclinical candidate, both as monotherapy and in combination with anti-TB agents for MDR-TB. We will also conduct pharmacokinetic studies, GLP toxicology and safety pharmacology studies to select a final anti-MDR/XDR clinical candidate suitable for IND submission.
TB is 1) highly infectious - it is disseminated via aerosols;2) virulent - it causes nearly 2 million deaths per year worldwide;and 3) widespread - one-third of the world's population is estimated to be infected with latent TB. Treatment of TB, especially, has become problematic due to difficulties with patient adherence to the extensive treatment period, increased incidence of MDR/XDR strains and increased coinfection with HIV/AIDS. We propose to develop a novel chemical class of TB therapeutic agents, the spectinamide series, for use against MDR and XDR strains of Mtb and identify, through a series of in vitro and in vivo assays, a preclinical candidate.
