Novel Spectinamide Antibiotics for the Treatment of MDR/XDR Tuberculosis

Summary/AbstractThe 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-quarter 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. As demonstrated in Phase I of the project, the novel spectinomycin analog and key spectinamides, possess potent in vitro activity against MDR/XDR TB, demonstrate efficacy in both acute and subacute murine models of TB infection, and are safe compounds, displaying low in vitro cytotoxicity and no observed in vivo toxicity. In Phase II, we identified MBX 4888 as the preclinical candidate, with similar efficacy to other lead compounds but with an improved safety profile. In Phase IIb, we will, in conjunction with our collaborators, Drs. Richard Lee, Greg Robertson and Anne Lenaerts, continue to evaluate in vivo efficacy in mice (inhalational dosing). We will also conduct pharmacokinetic studies, GLP toxicology and safety pharmacology studies in two species as well as manufacturing of non-GMP and GMP lots of material sufficient to complete preclinical and Phase I clinical studies. Finally, we will schedule a pre-IND meeting with the FDA and the South African authorities 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 inhalational, write an IND application and initiate Phase I clinical trials. These overall characteristics advocate for the rapid development of MBX 4888 as a safe alternative treatment for drug resistant TB.NarrativeTB is 1) highly infectious—it is disseminated via aerosols; 2) virulent—it causes nearly 2 million deaths per year worldwide; and 3) widespread —one-quarter 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 MBX 4888, 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.