Analysis of effects of MCB3681, the antibacterially active substance of prodrug MCB3837, on human resident microflora as proof of principle

Abstract

The water-soluble prodrug MCB3837 is rapidly converted to MCB3681, active against Gram-positive bacterial species, after intravenous infusion. The aim of this study was to prove the principle that MCB3681 is efficacious in vivo by demonstrating its effect on the resident microflora or colonizers of the human skin, nose, oropharynx and intestine. MCB3837 was infused at a daily dose of 6 mg/kg for 5 days. MCB3681 was active against clostridia, bifidobacteria, lactobacilli, enterococci and Staphylococcus aureus, thus proving the principle that MCB3681 is antibacterially efficacious in vivo without affecting the Gram-negative microflora.

In Vitro Activities of MCB3681 and Eight Comparators against Clostridium difficile Isolates with Known Ribotypes and Diverse Geographical Spread

“…Reduced metronidazole susceptibility (MIC = 4 mg/liter) was observed in only 1% of isolates. GM metronidazole MICs were elevated in RT027 (0.96 mg/liter) and RT106 (0.74 mg/liter) versus the GM metronidazole MIC for all isolates tested (0.33 mg/liter), in agreement with previous data ( 4 ).…”

“…MCB3681 is a novel small molecule with structural elements of an oxazolidinone and a quinolone showing good activity against C. difficile , including isolates that were resistant to linezolid, ciprofloxacin, moxifloxacin, and clindamycin ( 3 ). It achieves high fecal concentrations after intravenous infusions and has shown activity against Gram-positive components of the gut microflora in a clinical phase 1 study ( 4 ). The development of an intravenous treatment agent achieving high fecal concentrations would circumvent issues of rapid gut transit or of impaired delivery of orally administered agents due to ileus, particularly in patients with severe or protracted/multiple recurrent diarrheal episodes.…”

Recent updates of fluoroquinolones as antibacterial agents

“…The oxazolidinone‐ciprofloxacin conjugate 60 showed excellent in vitro activity against all tested strains including fluoroquinolone and/or vancomycin‐ and/or linezolid‐resistant isolates with MIC of 0.125–4 μg/mL and MIC: 0.25–0.5 μg/mL against fluoroquinolone‐ and/or vancomycin‐resistant isolates . Therefore, this kind of hybrids may provide new compounds with potential to fight against drug‐resistant, multidrug‐resistant, and pan‐drug resistant bacteria …”

Novel therapies and preventative strategies for primary and recurrent Clostridium difficile infections

“…It has been shown to have activity against Gram‐positive bacteria, including C. difficile , but limited activity against Gram‐negative bacteria such as those native to the human gut . A phase I study where 12 healthy volunteers were given daily intravenous infusions of 6 mg/kg MCB3837 over 12 h for 5 days showed little impact on microbiota and suggested the drug was well tolerated . Phase II/III trials are being planned currently, and the U.S. Food and Drug Administration (FDA) designated MCB3837 as a Qualified Infectious Disease Product for the treatment of CDI…”

“…[78][79][80] A phase I study where 12 healthy volunteers were given daily intravenous infusions of 6 mg/kg MCB3837 over 12 h for 5 days showed little impact on microbiota and suggested the drug was well tolerated. 81 Phase II/III trials are being planned currently, and the U.S. Food and Drug Administration (FDA) designated MCB3837 as a Qualified Infectious Disease Product for the treatment of CDI. 82 Nitazoxanide is believed to be a noncompetitive inhibitor of the pyruvate ferredoxin/flavodoxin oxidoreductases produced by Romark Pharmaceuticals.…”