Abstract
Drug resistant bacteria are winning the fight over antibiotics with some bacteria not responding to any antibiotics, threatening modern medicine as we know it. The development of new, effective and safe antibiotics is critical for addressing this issue. Ramizol, a first-in-class styrylbenzene based antibiotic, is an investigational drug indicated for Clostridium difficile infections (CDI). The objective of this range-finding study was to evaluate the potential general toxicity (based on toxicological endpoints selected) and toxicokinetics of Ramizol in male and female rats that may arise from repeated exposure via oral gavage over a test period of at least 14 days at doses of 50 mg/kg, 500 mg/kg and 1500 mg/kg. There were no mortalities in this study and no Ramizol-related clinical observations. Additionally, there were no changes in mean body weight, body weight gain, food consumption or food efficiency for male and female rats attributable to Ramizol administration. The observed pharmacokinetic behavior showed the presence of Ramizol in plasma at 24 hours post-dosing combined with increasing AUC(0–24) values during the course of this study in groups administered 1500 mg/kg/day, which suggests that at least some dosing groups will show accumulation of compound during repeated dose studies. These toxicology results have shown Ramizol is well-tolerated at very high concentrations in rats and support the further drug development of Ramizol as a first-in-class antibiotic for the treatment of CDI.
Highlights
The discovery of antibiotics has been one of the greatest discoveries of modern medicine and has played a key role in extending our life expectancy
Even though Ramizol is toxic to bacteria, it shows no cytotoxicity in L929 cells[2] and no haemolytic activity in sheep erythrocytes up to 50 μg/mL, at 25 times the MIC90 of C. difficile[3]
As predicted from in silico modeling, we have previously shown that the antimicrobial potency of Ramizol is dependent on mechanosensitive ion channel of large conductance (MscL), representing the first success at designing a drug with specificity to MscL1
Summary
The discovery of antibiotics has been one of the greatest discoveries of modern medicine and has played a key role in extending our life expectancy. The in silico design of MscL ligands, has recently led to the discovery of a new class of antibiotics[1] This came about by developing a spatial map of the exposed oxygen atoms of amino acids, lining the gate of the MscL channel. Ramizol (registered trademark in Australia) is a first-in-class stilbene-based investigational antibiotic for the treatment of Clostridium difficile infections (CDI) It has activity against most drug-resistant Gram-positive bacteria but limited activity against Gram-negative species[1], reducing the likelihood of collateral damage to the gut microbiota. The low oral bioavailability for Ramizol suggest that the drug remained entirely in the gastrointestinal tract akin other non-systemic antibiotics such as vancomycin and fidaxomicin While this is ideal for non-systemic infections, other routes of drug administration such as SC would be required for targeting systemic infections to ensure a high enough plasma concentration. Non-specific interactions with these channels and especially the hERG, are the reason behind the cardiotoxicity of marcrolides, ketolides and fluoroquinolones[6]
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