Arietis has developed a platform technology to identify lead compounds acting specifically against Helicobacter pylori, the causative agent of peptic ulcer and gastric carcinoma. Roughly every other person carries the pathogen, and there are an estimated 1.5 million cases annually of active infection in the US. The currently-used triple therapy is a combination of a proton pump inhibitor and antimicrobials, usually amoxicillin and clarithromycin. Increased incidence of resistance combined with poor tolerance of the regimen in some patients’ results in a treatment failure rate of 15-25%. An estimated 70% of patients who fail triple therapy develop antibiotic resistance. Considering the total number of cases, treatment failure is very high, and there is an urgent need for novel, more effective antimicrobials to combat this important disease. The common focus on broad-spectrum compounds is dictated by the need to treat diseases with uncertain causes, and the market dictates developing broad spectrum antibiotics as well. However, in the case of H. pylori, the disease is caused by a single pathogen and identification of specific agents will allow targeted therapy, without the unintended consequences of treatment with broad-spectrum agents. Arietis’s platform screening technology has allowed us to identify a number of excellent potent and specific leads for further development.
Arietis has also licensed technology to identify species-specific compounds against Clostridium difficile. C. difficile is the major cause of antibiotic-associated diarrhea and infection often leads to relapse, and can result in serious complications such as pseudomembranous colitis or death. Thus far, numerous lead molecules have been identified that are lethal and specific to the pathogen. These compounds are advantageous compare to broad-spectrum antibiotics which harm the normal intestinal microflora and contribute to disease. Such compounds have a broad spectrum marketing appeal since they will be administered along with traditional antibiotics, allowing “good” bacteria to rebound and out-compete the pathogen.
There is also a great need for new broad-spectrum antibiotics and new approaches for their discovery. None of the modern high-tech approaches is working. None has been productive for a decade or longer. Prodrug antibiotics provide a workaround to the broad-spectrum dilemma. Prodrug antibiotics are pathogen-activated compounds where the final active moiety is produced within the bacterium. The biggest difference between a prodrug antibiotic, and a typical antibiotic, is the method of production: instead of chemical reactors, biological reactors create the product; the technology puts bacterial cells to work for drug production purposes.
The biggest challenge with the discovery of prodrug antibiotics has been attainment of a single compound that possesses a potent warhead as well as the appropriate properties that permit penetration to the target site. This has proven unachievable even with modern day target-based technology. The primary reason for this is the remarkable versatility of bacterial armor - permeability barriers, and the ability of microbes to remove drug products they are exposed to. Because prodrug antibiotics are produced within the bacterium, what gets transported and what remains active, within the bacterium, against the target are two distinct entities. As such, prodrugs open a whole new dimension for chemical exploitation since penetration features can be chemically separated from the warhead. The warhead will function inside the pathogen, reducing host exposure to the active entity.
Similarly there is a great need for new antifungal agents. The primary targets for drug development here are “persister” cells. Persisters are variants of the wild type that are present in all bacterial and fungal species studied. They vary in terms of gene expression, manifesting different physical characteristics, but are not mutants; upon re-growth they produce a population with a bulk of sensitive cells and a new persister fraction. They have been found to populate a specific biological entity, the biofilm.
Fungal biofilms are communities of cells that settle and proliferate on surfaces and are covered by a biological matrix. They are slow growing or even completely stationary. Persister cells that are contained in the biofilm can survive both the onslaught of antifungal treatment and the immune system. When antifungal levels decrease, these persister cells can repopulate the biofilm, which will shed off new actively growing cells, producing a relapsing infection. Fungal biofilm infections are highly recalcitrant to antifungal treatment. The key to providing a completely efficacious therapy is to combine a molecule that disables the mechanism of persister formation or maintenance, a “potentiator”, that can synergize with a conventional antimicrobial and lead to eradication of the pathogen.
Antifungal persister populations have not previously been addressed in drug development despite being the cause of therapeutic failure. Moreover, prodrug antibiotic precedents exist from the 1950s, providing validation for the approach. Systematic efforts over the past 60 years searched for everything except prodrug antibiotics (with diminishing returns), inadvertently screening against such compounds. The clinical need and commercial opportunity remain at a high point with pan-resistant and multidrug resistant pathogens. Although the Arietis approach is novel, the antimicrobial development path is well-defined and straightforward, with animal models extremely predictive of clinical outcome, making this a very attractive therapeutic space.