? DESCRIPTION (provided by applicant): 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 potentially damaging inflammation. Currently-used antibiotics can kill organisms, but the effectiveness of anti-inflammatory drugs is controversial. These drug classes do not target tissue-damaging toxins synthesized by bacteria at the site of infection. Pore-forming toxins (PFTs) are important, and often essential, to ocular virulence of the following Gram-positive ocular pathogens: Staphylococcus aureus, Streptococcus pneumoniae, Bacillus cereus, and Enterococcus faecalis. When PFTs are absent, ocular virulence is significantly decreased. Novel PFT-targeting therapeutics which neutralize toxins across species would provide coverage for the most common Gram-positive pathogens causing ocular surface (keratitis) and intraocular (endophthalmitis) infections. Toxin neutralization as an adjunct with antibiotics and anti-inflammatory agents would provide a significant improvement over current therapies that are ineffective against tissue-damaging toxins. Nanosponges have recently been developed which target Gram-positive PFTs. In vitro, nanosponges neutralize Gram-positive PFTs. In in vivo experimental models of sepsis and tissue infection, nanosponges neutralize toxins at the site of infection and reduce virulence. We hypothesize that nanosponges can effectively reduce the toxic activity of bacterial PFTs in the ocular environment, leading to use as a novel anti-toxi therapeutic with antibiotics for the treatment of intraocular and ocular surface infections. Preliminary data demonstrates the feasibility of testing our hypothesis. We show that nanosponges 1) neutralize PFTs of Gram-positive ocular pathogens, 2) do so in the presence of tears, vitreous, and antibiotics, 3) protect against toxic ocular cell death, and 4) are not toxic in/on mouse eyes. A critical barrier to clinical improvements in ocular bacterial infections is th absence of toxin- targeting. We will test nanosponges for PFT-neutralizing activity and efficacy with antibiotics against ocular pathogens causing keratitis (Aim 1) and endophthalmitis (Aim 2), and will also investigate their biodistribution following ocular application (Aim 3). If nanosponge are effective, the next step is to test nanosponges with more potent antibiotics and better anti-inflammatory agents. Testing of nanosponges in the treatment of ocular bacterial infections is high risk, but is novel, high-impact, translationally relevant, and will positively influence the ocular infectious disease field by identifying a novel anti-toxin therapy which may protect delicate tissues of the eye during infection. The proposed studies are a logical outgrowth of our ocular infection research program, and we are well positioned to contribute valuable information which will provide physicians with the best possible therapeutic options to preserve vision during ocular infections.

R01EY025947

2015-09-30

2019-08-31