MBX-500, a hybrid antibiotic with in vitro and in vivo efficacy against toxigenic Clostridium difficile

Abstract

Clostridium difficile infection (CDI) causes moderate to severe disease, resulting in diarrhea and pseudomembranous colitis. CDI is difficult to treat due to production of inflammation-inducing toxins, resistance development, and high probability of recurrence. Only two antibiotics are approved for the treatment of CDI, and the pipeline for therapeutic agents contains few new drugs. MBX-500 is a hybrid antibacterial, composed of an anilinouracil DNA polymerase inhibitor linked to a fluoroquinolone DNA gyrase/topoisomerase inhibitor, with potential as a new therapeutic for CDI treatment. Since MBX-500 inhibits three bacterial targets, it has been previously shown to be minimally susceptible to resistance development. In the present study, the in vitro and in vivo efficacies of MBX-500 were explored against the Gram-positive anaerobe, C. difficile. MBX-500 displayed potency across nearly 50 isolates, including those of the fluoroquinolone-resistant, toxin-overproducing NAP1/027 ribotype, performing as well as comparator antibiotics vancomycin and metronidazole. Furthermore, MBX-500 was a narrow-spectrum agent, displaying poor activity against many other gut anaerobes. MBX-500 was active in acute and recurrent infections in a toxigenic hamster model of CDI, exhibiting full protection against acute infections and prevention of recurrence in 70% of the animals. Hamsters treated with MBX-500 displayed significantly greater weight gain than did those treated with vancomycin. Finally, MBX-500 was efficacious in a murine model of CDI, again demonstrating a fully protective effect and permitting near-normal weight gain in the treated animals. These selective anti-CDI features support the further development of MBX 500 for the treatment of CDI.

Fig 1

Structure of MBX-500, a hybrid of an anilinuracil (AU) DNA polymerase inhibitor and a fluoroquinolone (FQ) DNA topoisomerase/gyrase inhibitor.

Fig 2

Percentage of survival over 6 days of acute C. difficile infection in hamsters. Diamonds, vehicle-treated control; squares, vancomycin, 50 mg/kg; triangles, MBX-500, 50 mg/kg.

Fig 3

Percentage of survival (A) and mean relative weight (B) measurements over 29 days of acute and recurrent C. difficile infection in hamsters. Diamonds, uninfected, untreated control; squares, vehicle-treated control; triangles, vancomycin, 50 mg/kg; circles, MBX-500, 200 mg/kg. Error bars indicate standard errors of the data in panel B, and statistical analysis was performed using the Student t test set for the “two-sample assuming unequal variances” assumption.

Fig 4

Outcome over 12 days of acute and recurrent C. difficile infection in mice. (A) Percent survival; (B) mean weight. Diamonds, untreated control; squares, MBX-500, 100 mg/kg once daily; circles, vancomycin, 50 mg/kg once daily.