sq-641 and capuramycin

Clostridium difficile infection (CDI) is a primary cause of antibiotic-associated diarrhoeal illness. Current therapies are insufficient as relapse rates following antibiotic treatment range from 25% for initial treatment to 60% for treatment of recurrence. In this study, we looked at the efficacy of SQ641 in a murine model of CDI. SQ641 is an analogue of capuramycin, a naturally occurring nucleoside-based compound produced by Streptomyces griseus.. In a series of experiments, C57BL/6 mice were treated with a cocktail of antibiotics and inoculated with C. difficile strain VPI10463. Animals were treated orally with SQ641 for 5 days at a dose range of 0.1-300 mg/kg/day, 20 mg/kg/day vancomycin or drug vehicle. Animals were monitored for disease severity, clostridial shedding and faecal toxin levels for 14 days post-infection.. Five day treatment of CDI with SQ641 resulted in higher 14 day survival rates in mice compared with either vancomycin or vehicle alone. CDI survival rates were 100% (13 of 13) and 94% (32 of 34), respectively, in the 1 and 10 mg/kg/day SQ641 treatment groups, 37% (7 of 19) with vancomycin treatment at 20 mg/kg/day and 32% (14 of 44) in the vehicle-only control group. Secondary measures of efficacy, such as prevention of weight loss, decreased disease severity, decreased C. difficile shedding and decreased toxin in faeces, were observed with SQ641 and vancomycin treatment.. SQ641 is effective for CDI treatment with prevention of relapse in the murine model of CDI.

Topics: Administration, Oral; Aminoglycosides; Animals; Anti-Bacterial Agents; Bacterial Shedding; Bacterial Toxins; Clostridioides difficile; Disease Models, Animal; Enterocolitis, Pseudomembranous; Feces; Male; Mice, Inbred C57BL; Severity of Illness Index; Survival Analysis; Treatment Outcome; Uridine

Capuramycin (1) and its analogs are strong translocase I (MurX/MraY) inhibitors. In our structure-activity relationship studies of capuramycin analogs against Mycobacterium tuberculosis (Mtb), we observed for the first time that a capuramycin analog, UT-01320 (3) killed nonreplicating (dormant) Mtb at low concentrations under low oxygen conditions, whereas selective MurX inhibitors killed only replicating Mtb under aerobic conditions. Interestingly, 3 did not exhibit MurX enzyme inhibitory activity even at high concentrations, however, 3 inhibited bacterial RNA polymerases with the IC50 values of 100-150 nM range. A new RNA polymerase inhibitor 3 displayed strong synergistic effects with a MurX inhibitor SQ 641 (2), a promising preclinical tuberculosis drug.

Topics: Aminoglycosides; Antitubercular Agents; Bacterial Proteins; Caprolactam; DNA-Directed RNA Polymerases; Drug Synergism; Enzyme Inhibitors; Inhibitory Concentration 50; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Oxygen; Structure-Activity Relationship; Transferases; Transferases (Other Substituted Phosphate Groups); Uridine

Acylated derivatives of capuramycin and A-500359A were synthesized and tested for antimycobacterial activity. Compound 20 having a decanoyl group showed very potent activity.

Topics: Acylation; Aminoglycosides; Anti-Bacterial Agents; Enzyme Inhibitors; Inhibitory Concentration 50; Isomerism; Microbial Sensitivity Tests; Mycobacterium; Prodrugs; Structure-Activity Relationship; Transferases