RESUMO
Spectinamides are a novel class of narrow-spectrum antitubercular agents with the potential to treat drug-resistant tuberculosis infections. Spectinamide 1810 has shown a good safety record following subcutaneous injection in mice or infusion in rats but exhibits transient acute toxicity following bolus administration in either species. To improve the therapeutic index of 1810, an injectable prodrug strategy was explored. The injectable phosphate prodrug 3408 has a superior maximum tolerated dose compared to 1810 or Gentamicin. Following intravenous administration in rodents, prodrug 3408 was quickly converted to 1810. The resulting 1810 exposure and pharmacokinetic profile after 3408 administration was identical to equivalent molar amounts of 1810 given directly by intravenous administration. 3408 and the parent 1810 exhibited similar overall efficacy in a BALB/c acute tuberculosis efficacy model. Delivery of 1810 in phosphate prodrug form, therefore, holds the potential to improve further the therapeutic index of an already promising tuberculosis antibiotic.
Assuntos
Antituberculosos , Camundongos Endogâmicos BALB C , Pró-Fármacos , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Pró-Fármacos/química , Animais , Antituberculosos/síntese química , Antituberculosos/farmacologia , Antituberculosos/química , Antituberculosos/farmacocinética , Camundongos , Ratos , Testes de Sensibilidade Microbiana , Espectinomicina/farmacologia , Espectinomicina/síntese química , Espectinomicina/química , Fosfatos/química , Fosfatos/farmacologia , Fosfatos/síntese química , Mycobacterium tuberculosis/efeitos dos fármacos , Estrutura Molecular , Relação Dose-Resposta a Droga , Relação Estrutura-AtividadeRESUMO
AN12855 is a direct, cofactor-independent inhibitor of InhA in Mycobacterium tuberculosis In the C3HeB/FeJ mouse model with caseous necrotic lung lesions, AN12855 proved efficacious with a significantly lower resistance frequency than isoniazid. AN12855 drug levels were better retained in necrotic lesions and caseum where the majority of hard to treat, extracellular bacilli reside. Owing to these combined attributes, AN12855 represents a promising alternative to the frontline antituberculosis agent isoniazid.
Assuntos
Antituberculosos/farmacologia , Compostos Aza/farmacologia , Compostos de Boro/farmacologia , Hidrocarbonetos Fluorados/farmacologia , Inibinas/antagonistas & inibidores , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose Pulmonar/tratamento farmacológico , Animais , Carga Bacteriana/efeitos dos fármacos , Modelos Animais de Doenças , Desenvolvimento de Medicamentos , Feminino , Isoniazida/farmacologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C3H , Testes de Sensibilidade Microbiana , Tuberculose Pulmonar/microbiologiaRESUMO
There is urgent need for new drug regimens that more rapidly cure tuberculosis (TB). Existing TB drugs and regimens vary in treatment-shortening activity, but the molecular basis of these differences is unclear, and no existing assay directly quantifies the ability of a drug or regimen to shorten treatment. Here, we show that drugs historically classified as sterilizing and non-sterilizing have distinct impacts on a fundamental aspect of Mycobacterium tuberculosis physiology: ribosomal RNA (rRNA) synthesis. In culture, in mice, and in human studies, measurement of precursor rRNA reveals that sterilizing drugs and highly effective drug regimens profoundly suppress M. tuberculosis rRNA synthesis, whereas non-sterilizing drugs and weaker regimens do not. The rRNA synthesis ratio provides a readout of drug effect that is orthogonal to traditional measures of bacterial burden. We propose that this metric of drug activity may accelerate the development of shorter TB regimens.