According to the World Health Organization (WHO), multidrug-resistant (MDR) bacterial pathogens, commonly known as “superbugs”, are among the most serious threats to public health.1,2
Bacteria are developing resistance to all known antibiotics,3,4 and the rate of resistance development is occurring at a faster pace than pharmaceutical companies are able to introduce new drugs to market. Even when novel antibiotics are discovered, resistant strains of bacteria rapidly evolve,5 and it is becoming more and more difficult for drug makers to develop products that will effectively treat MDR bacterial infections.6
Antibiotic-resistant bacteria cause more than two million infections per year in the US, resulting in ~20,000 deaths. These infections result in an estimated $20 billion in direct healthcare costs and $35 billion in lost productivity7 and these costs are expected to rise rapidly over the next several years.8 The threat of antibiotic resistance is especially critical in the case of Gram-negative bacterial pathogens, such as Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae.
Infections caused by MDR Gram-negative bacteria result in a higher mortality rate, longer hospital stays and larger treatment costs compared to antibiotic-susceptible infections. Patients with MDR Gram-negative bacterial infections have a mortality rate of 30-70%,9 which is approximately two to three-fold higher than patients who have an antibiotic-susceptible infection.10
Clearly, a new effective treatment for MDR Gram-negative bacterial infections would provide an immediate, desperately needed solution to one of the most dire problems impacting global health.
Agile Sciences’ 2-AI molecules have the potential to overcome bacterial resistance elements so as to restore the efficacy of multiple antibiotics that are currently inactive against MDR Gram-negative bacterial strains. The 2-AI molecules are widely active across multiple bacterial species, and are able to effectively overcome multiple antibiotic resistance mechanisms. Therefore, these molecules have the potential to provide clinicians with a substantially improved method for treating MDR Gram-negative bacterial infections.
Agile Sciences is currently evaluating the spectrum of activity of a lead compound for this application. The lead compound, AGL-503, was able to restore the activity of meropenen against a carbapenem-resistant strain of Pseudomonas aeruginosa in an acute murine lung infection model. Additionally, a medicinal chemistry program is underway to identify additional compounds.