rifamycin-sv and Disease-Models--Animal

A new rifamycin derivative 3-(4-cinnamyl-piperazinyl iminomethyl) rifamycin SV (T9) and its sodium salt (T11, Rifacinna((R))) were in vitro, in vivo, toxicologically and clinically investigated in comparison with rifampicin, rifapentine, rifabutin, rifalazil. Our experiments showed that Rifacinna exhibits excellent in vitro activity against Gram(+), Gram (-) aerobic, anaerobic pathogens and mycobacteria. Rifacinna is active against Staphylococcus, Streptococcus spp. including MRSA, with MIC90- 0.06-0.5 mg/L; against Gram(+), Gram (-) anaerobes with MIC90 0.5 - 1 mg/L; against Mycobacterium tuberculosis (MTB) with MIC90 0.062 mg/L; against MDR resistant MTB (25%-30 %) and Mycobacterium avium complex (MAC) strains with MICs 0.6-1.0 mg/L. It shows high intraphagocytic activity against MAC strains (0.06 0.125mg/L). Single daily dose 10 mg/kg provides complete erradication of mycobacteria in experimental generalized tuberculosis. Pharmacological studies established: excellent pharmacokinetic profile following single oral dose 10mg/kg Tmax 5-6 h, C(max) 5-9 mg/L, T1/2 33-34 h; low toxicity; no teratogenic and embryotoxic effects. The clinical study of Rifacinna shows higher therapeutic efficacy than Rifampicin in patients with infiltrative, disseminated and cavitary form of pulmonary tuberculosis, good tolerability and safety profile. Some of the recent patents related to the treatment of tuberculosis are discussed in this review article.

Topics: Animals; Antibiotics, Antitubercular; Disease Models, Animal; Humans; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium; Rifamycins; Structure-Activity Relationship; Toxicity Tests; Treatment Outcome; Tuberculosis

In a previous report, we described the discovery of 1,4-azaindoles, a chemical series with excellent in vitro and in vivo antimycobacterial potency through noncovalent inhibition of decaprenylphosphoryl-β-d-ribose-2'-epimerase (DprE1). Nevertheless, high mouse metabolic turnover and phosphodiesterase 6 (PDE6) off-target activity limited its advancement. Herein, we report lead optimization of this series, culminating in potent, metabolically stable compounds that have a robust pharmacokinetic profile without any PDE6 liability. Furthermore, we demonstrate efficacy for 1,4-azaindoles in a rat chronic TB infection model. We believe that compounds from the 1,4-azaindole series are suitable for in vivo combination and safety studies.

Topics: Alcohol Oxidoreductases; Animals; Antitubercular Agents; Bacterial Proteins; Cyclic Nucleotide Phosphodiesterases, Type 6; Disease Models, Animal; Humans; Indoles; Mice; Mycobacterium tuberculosis; Oxidoreductases; Rats; Structure-Activity Relationship

The activities of a range of antibiotics on Staphylococcus aureus organisms that survive within bovine neutrophils in vitro were studied in mice. Cloxacillin, floxacillin, and cephradine failed to kill intracellular staphylococci but increased the organisms' sensitivity to killing by lysostaphin after neutrophil disruption. Fusidate and clindamycin caused an apparent small reduction in viable intraleukocytic S aureus, whereas novobiocin did not demonstrate intracellular activity. Substantial intracellular bactericidal effects were shown in vitro by rifampin and rifamycin SV, even at concentrations in slight excess of the minimum inhibitory concentration. In a mouse model of chronic mastitis, intramammary therapy with rifampin was more effective in reducing viable S aureus in infected glands than was therapy with rifamycin SV.

Topics: Animals; Anti-Bacterial Agents; Cattle; Cloxacillin; Disease Models, Animal; Drug Therapy, Combination; Female; Leukocytes; Lysostaphin; Mastitis; Mastitis, Bovine; Mice; Neutrophils; Penicillin Resistance; Pregnancy; Rifampin; Rifamycins; Rodent Diseases; Staphylococcal Infections; Staphylococcus aureus