The overall objective of this project is to 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 vivo efficacy assays and preclinical pharmacokinetics, toxicology and safety pharmacology studies, a clinical 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 T 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. As demonstrated in Phase I of the project, the novel spectinomycin analog and preclinical candidate, Lee 1599, possesses potent in vitro activity against MDR/XDR TB (MIC90 1.2 ?g/mL), demonstrates efficacy in both acute and subacute murine models of TB infection, and is a safe compound, displaying low in vitro cytotoxicity and no observed in vivo toxicity. These overall characteristic advocate for the rapid development of this compound as a safe alternative treatment for drug resistant TB. In Phase II, we will, in conjunction with our collaborators, Drs. Richard Lee and Anne Lenaerts, continue to evaluate in vivo efficacy in mice (combination trials, ability to preven recurrence and efficacy in a chronic infection model). We will then conduct pharmacokinetic studies, GLP toxicology and safety pharmacology studies in two species as well as final process chemistry, leading to manufacturing of a GMP lot of material. Finally, we will schedule a pre-IND meeting with the FDA in preparation for an IND filing. In Phase III, we will meet all remaining FDA requirements, continue to explore alternative routes of administration such as intravenous, intramuscular and inhalational, write an IND application and initiate Phase I clinical trials.
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 compound 1599, a preclinical candidate member of a novel chemical class of TB therapeutic agents, the spectinamide series, for use against MDR and XDR strains of Mtb and produce, through a series of IND-enabling preclinical studies, a clinical candidate.
|Robertson, Gregory T; Scherman, Michael S; Bruhn, David F et al. (2017) Spectinamides are effective partner agents for the treatment of tuberculosis in multiple mouse infection models. J Antimicrob Chemother 72:770-777|