The leading cause of mortality in patients with cystic fibrosis (CF) is pulmonary failure from lung infections, and the predominant organism isolated from these infections is the bacterium Pseudomonas aeruginosa. Lung infections of CF patients persist over the lifetime of the patients, and are impossible to eradicate due to the ability of bacteria to form biofilms and to express multidrug resistance elements. Biofilms are surface-attached communities of bacteria that are surrounded by a protective matrix. Bacteria in biofilms are upwards of 1000 times more resistant to currently used antimicrobials than free-floating bacteria. In addition to the ability of P. aeruginosa to form biofilms, the bacterium is known to rapidly acquire resistance to antibiotics to form multidrug resistant (MDR) strains. Due to the inherent limitations of current therapies to effectively eliminate P. aeruginosa biofilms and MDR P. aeruginosa from the lungs of CF patients, an improved therapeutic option is needed that addresses these underlying reasons for treatment failure. In Phase I, Agile Sciences identified a lead 2-aminoimidazole (2-AI) compound, AGL-503, that is effective at dispersing MDR P. aeruginosa biofilms in vitro and in vivo and enhancing antibiotic efficacy toward MDR P. aeruginosa as measured by a lowering of the MIC value of the antibiotic. AGL-503 is a small organic molecule that acts via a novel mechanism of action and possesses therapeutically desirable permeability, toxicity, and metabolic stability properties. Furthermore, in an in vivo evaluation in Dr. Richard Boucher's lab at the University of North Carolina at Chapel Hill, AGL-503 was shown to disrupt biofilm-like aggregates of bacteria within the lungs of mice. In Phase II of this STTR project, a medicinal chemistry effort will be used in Aim 1 to enhance the activity seen with AGL-503. Agile Sciences has assembled a team of pharmaceutical experts in the areas of microbiology, organic chemistry, pharmacokinetics/pharmacodynamics, toxicity, and pre-clinical development to guide the medicinal chemistry program. The optimal antibiotic/2-AI combination identified in Aim 1 will be further evaluated in Aim 2 using Dr. Boucher's murine model to maximize the efficacy of the combination treatment. Specific variables to be evaluated include route of administration as well as dosing schedule. Dr. Matt Wolfgang will join the Phase II team as a co-investigator, adding additional expertise in P. aeruginosa lung infection models. Upon completion of this work, Agile Sciences expects to have identified a candidate 2-AI molecule that will then enter a preclinical development program consisting of GLP safety assessments to enable IND submission to the FDA and subsequent clinical trials. The novel therapy developed in this Phase II work has the potential to substantially enhance current therapeutic performance toward recalcitrant P. aeruginosa lung infections in the lungs of CF patients, thereby increasing the quality of life and life expectancy of these individuals.
The primary cause of mortality of CF patients is complications associated with untreatable lung infections. The difficulty in treating these infections is due bot to the presence of biofilms, which are communities of bacteria surrounded by a protective matrix, and to the arsenal of drug resistance enzymes the bacteria harbor. This project addresses the inherent limitations of antibiotic therapies for CF patients by co-dosing the antibiotics with a novel adjuvant therapeutic that is capable of disrupting biofilms and enhancing the effectiveness of the antibiotic.