MBX-500, a Hybrid Antibiotic with In Vitro and In Vivo Efficacy against Toxigenic Clostridium difficile

Abstract

f 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 nearnormal weight gain in the treated animals. These selective anti-CDI features support the further development of MBX 500 for the treatment of CDI.

Effect of the Synthetic Bile Salt Analog CamSA on the Hamster Model of Clostridium difficile Infection

“…In our hands, the antigerminant CamSA has lower efficacy in protecting hamsters from C. difficile strain 630, compared to mice; this finding is not unexpected. Previous reports have consistently shown that CDI treatment in hamsters results in worse outcomes than in a corresponding mouse model (36)(37)(38)(39). Furthermore, treatment efficacy is dependent on the C. difficile strain used in the hamster model (40).…”

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“…The MTD approach is also being used to combat the development of resistance to antimicrobials. MBX-500 has been designed as a hybrid of two classes of antibiotics, fluoroquinolone and anilinouracil, for the treatment of Clostridium difficile infections (Butler et al, 2012 ). TD-1792, a cephalosporin-vancomycin hybrid, has passed a phase II clinical trial for gram-positive skin infections (Stryjewski et al, 2012 ).…”

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“…The narrow spectrum of fidaxomicin is believed to contribute to its favourable characteristics in treating recurrent CDI, 89 but the effect of kibdelomycin on recurrent disease has not been investigated yet. MBX-500 also had little activity against most Gram-negative anaerobes, and was selectively active against C. difficile strains among Gram-positive anaerobes 75 . MBX-500 was shown to be efficacious in a gnotobiotic piglet model of acute CDI, with a 100% survival rate and only mild CDI symptoms 99 .…”

“…MBX-500 was shown to be efficacious in a gnotobiotic piglet model of acute CDI, with a 100% survival rate and only mild CDI symptoms 99 . Though the efficacy of MBX-500 was comparable to that of vancomycin in a hamster model of CDI, it was superior in a murine model of recurrent CDI and associated with improved weight gain in both animal models 75 . The weight gain of infected animals treated with MBX-500 and the results in the murine model suggest that this compound might have a low impact on the gut microbiota.…”