Novel spectinamide antibiotics for the treatment of MDR/XDR tuberculosis

DESCRIPTION provided by applicant 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 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 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 possesses potent in vitro activity against MDR XDR TB MIC 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 PUBLIC HEALTH RELEVANCE TB is highly infectious it is disseminated via aerosols virulent it causes nearly million deaths per year worldwide and widespread one third of the worldandapos 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 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