Research Project
10384258
PROJECT SUMMARY / ABSTRACT The goal of this project is to develop a new, effective treatment for chronic suppurative otitis media (CSOM), a currently uncurable condition involving severe, chronic middle ear infection. CSOM is the most common cause of persistent hearing loss for children in the developing world, and affects 330 million people worldwide. It is characterized by a chronically infected, discharging middle ear, and currently has no effective medical therapy. The bacterium Pseudomonas aeruginosa (PA) is a leading cause of CSOM, and colonizes the middle ear via a perforated tympanic membrane, where it becomes established into a biofilm community. The current primary treatment modality for CSOM, fluoroquinolone (usually ofloxacin) eardrops, is ineffective in completely eliminating CSOM infection, apparently due to an inability to target the subpopulation of metabolically inactive bacteria within the biofilm known as ?persister cells?. These persister cells repopulate the biofilm niche after the fluoroquinolone therapy is discontinued, causing CSOM to relapse. This interdisciplinary project leverages the combined expertise of the Santa Maria lab, which has created a mouse model for CSOM with PA biofilms and has recent middle ear translational success, and the Barron lab, which develops antimicrobials. Our innovative approach involves the design, synthesis, optimization and in vivo testing of uniquely biostable analoguesof natural antimicrobial peptides (AMPs). AMPs are natural defense mechanisms to combat infectious agents in vivo, and some are effective against biofilms; yet their poor bioavailability (i.e. rapid in vivo proteolytic degradation) limits their clinical use. We will utilize AMP mimics based which are sequence- and length-specific oligo-N-substituted glycine mimics of natural polypeptides. on peptoids, Peptoids are based on a polypeptide backbone; yet have side-chains appended to backbone nitrogens. Because of this structural difference, peptoids are completely stable to proteolysis. Furthermore, they can be made in high yields at reasonable cost, using an automated peptide synthesizer. Synthetic Antimicrobial Peptoids (SAMPs) are potent drugs that can completely eliminate persisters in biofilms. Our preliminary data show that SAMPs are more effective than ofloxacin at killing planktonic persister cells and eradicating mature biofilms. Our aims are focused on optimizing our lead SAMP candidate and confirming efficacy in our CSOM mouse model. The Aims are: (1) in vitro screening of TM5 analogs modified to improve efficacy against clinical isolate persister cells and mature biofilms and (2) showing proof of concept that the lead SAMP can be effective in a CSOM mouse model while also being non-ototoxic. After finishing our final in vivo efficacy, we plan to proceed through preclinical translation. With Phase II support, our goals will be to show non-systemic toxicity, safety, distribution, pharmacokinetics, formulation, stability, and dose escalation to assemble an IND package.
