The goal of this program is to evaluate the small-molecule therapeutic agent CRS3123 for efficacy in a mouse model of H. pylori infection (HPI). Resistance to commonly used first- and second-line antibiotics to treat HPI is on the rise, resulting in a steady decrease of clinical efficacy. We are developing a novel mode-of-action agent with exquisite potency against HP. CRS3123 demonstrated good in vitro activity against all HP strains tested (MIC range of 0.06 - 1 g/mL and MIC90 = 0.5 g/mL), including a multidrug-resistant strain and the most pathogenic strains of the vacA s1-m1 and cagA-positive genotype. CRS3123 has already been demonstrated to be safe in humans in single dose and multiple ascending dose Phase I clinical studies toward its development as a novel agent to treat C. difficile infection. Limited systemic absorption and high accumulation of CRS3123 in the gut (>1,000 g/g in stool) has been observed, thus, we are confident that CRS3123 has the potential to accumulate to high levels at the site of HPI in the stomach. Furthermore, CRS3123 has a very narrow spectrum of activity with regard to gastrointestinal bacteria (H. pylori, Clostridia), thus sparing most beneficial constituents of normal gut microbiota. CRS3123 targets the bacterial MetRS enzyme and therefore inhibits protein synthesis. The immediate and effective blocking of de novo toxin production has already been demonstrated for C. difficile. CRS3123 is expected to inhibit production of HP toxins CagA and VacA in vitro as well, which may aide in the resolution of symptoms of HP-associated peptic ulcer disease. In addition, CRS3123 is expected to block the production of urease, which is essential for acid acclimation and survival of HP. Our approach will begin with an in-depth microbiological evaluation of CRS3123 against H. pylori, including the determination of spontaneous resistance rate and mutant prevention concentration. Drug combination studies will be performed to monitor in vitro synergy with common first- and second-line antibiotics typically used to treat HP infections. Pharmacokinetics and efficacy of CRS3123 will be assessed in the standard mouse model of HPI. Levels of CRS3123 will be determined in the stomach; we expect to see high accumulation of CRS3123 in the stomach and limited systemic exposure, concomitant with a reduction of the H. pylori burden. We believe that CRS3123, as a single agent or in combination with a proton pump inhibitor (PPI), represents an excellent potential alternative to currently approved regimens involving two or three antibiotics and a PPI, such as standard triple or quadruple therapy of HPI.
This proposal is in response to the enormous human health challenge created by H. pylori, a pathogen that causes over half a million stomach cancers worldwide per year. H. pylori has become increasingly resistant to treatment with a standard antibiotic regimen and we propose to develop a new antibiotic to meet this serious unmet medical need. Our approach is based on a novel antibacterial agent that has already been proven to be well-tolerated and safe in humans in Phase 1 clinical trials.
