PROJECT SUMMARY / ABSTRACT Ocular bacterial infections cause a significant number of cases of blindness worldwide. Efforts to prevent damage to delicate ocular tissues during infection rely on swift and proper use of therapeutics to rapidly kill organisms and arrest damaging inflammation. Mainstay antibiotics currently approved for ocular use can kill ocular pathogens. However, given the speed at which these infections can evolve, the emergence of multidrug resistant (MDR) ocular pathogens, the delicate nature of ocular tissue, and the importance of proper visual acuity, halting these infections as soon as possible is critical to patients? ocular health. Alternative antimicrobial strategies which result in rapid killing of organisms in the eye would provide a significant improvement over that of mainstay antibiotics which allow replication due to their slow activities, or antibiotics that are ineffective due to MDR pathogens. Bacteriophage-based therapeutics have gained traction as a last line experimental strategy for the treatment of patients infected with MDR pathogens. Efficacy testing of phages and, more recently, phage lysins, in treating bacterial infections is not new. However, their use in treating ocular infections of all types in a broad-spectrum regimen in eye infections has not been studied. Our goal is to create a phage lysin cocktail which can be administered to the eye during infection, resulting in rapid killing of those organisms, mitigation of inflammation, and preservation of vision. We hypothesize that because phage lysins rapidly lyse bacteria prior to phage exit, these lysins will rapidly kill bacteria in ocular tissues during infection. Preliminary data demonstrates feasibility and success in phage lysin-mediated killing of S. aureus in the eyes of mice. The next steps are to test the efficacy of phage lysins in killing other ocular bacterial pathogens in experimental models of keratitis and endophthalmitis (Aim 1), and then combine and test phage lysins of different bacteria in a broad-spectrum cocktail in these models against MDR pathogens (Aim 2). A critical barrier to clinical improvements in ocular bacterial infections is the use of mainstay antibiotics that may not kill efficiently enough. We have reported that regardless of the offending pathogen, bacterial replication in the eye triggers acute inflammation in response to an increasing innate immune agonist burden and results in toxin production which leads to tissue damage. These studies will determine whether phage lysins kill ocular pathogens more efficiently than mainstay antibiotics, resulting in improvements in therapeutic outcome. If effective, the next step is to test the phage lysin cocktails with innate pathway-based anti-inflammatory agents, which we are also pursuing. Testing of phage lysins in the treatment of ocular bacterial infections is novel, high-impact, translationally relevant, and will positively influence the ocular infectious disease field by identifying a more effective antimicrobial strategy for treating ocular infections, preventing blindness and benefitting patients afflicted with these infections.

R21EY031802

2020-08-01

2022-07-31