Transcriptomics and systems biology identify non-antibiotic drugs for the treatment of ocular bacterial infection

• Type of Material: Article
• Authors: Susmita Das, Kresge Eye Institute; Sukhvinder Singh, Kresge Eye Institute; Sarthak Satpathy, Emory University; Manoj Bhasin, Emory University; Ashok Kumar, Kresge Eye Institute
• Language: English
• Date: 2022-09-16
• Publisher: Elsevier
• Publication Version: Final Published Version
• Copyright Statement: © 2022 The Author(s)
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.isci.2022.104862
• Title of Journal or Parent Work: iScience
• Volume: 25
• Issue: 9
• Start Page: 104862
• End Page: 104862
• Grant/Funding Information: Our research is also supported in part by an unrestricted grant from Research to Prevent Blindness (RPB) to the Kresge Eye Institute/Department of Ophthalmology, Visual, and Anatomical Sciences; The immunology core is supported by an NEI center grant P30EY004068. The funders had no role in study design, data collection, and interpretation, or the decision to submit the work for publication.
• Keywords: microbiology; Medicine; applied microbiology
• Research Categories: Chemistry, Biochemistry; Biology, Microbiology; Health Sciences, Immunology

Abstract

Increasing antibiotic resistance among ocular pathogens often results in treatment failure for blinding infections such as endophthalmitis. Hence, newer therapeutics is needed to combat multidrug-resistant infections. Here, we show a drug repurposing approach using a connectivity map based on temporal transcriptomics of Staphylococcus aureus (SA) infected mouse retina. The analysis predicted three non-antibiotic drugs, Dequalinium chloride (DC), Clofilium tosylate (CT), and Glybenclamide (Glb) which reversed the SA infection signatures. Predicted drugs exhibited anti-inflammatory properties in human retinal cells against sensitive and resistant strains of SA. Intravitreal administration of all drugs reduced intraocular inflammation in SA-infected mouse eyes while DC and CT also reduced bacterial burden. Drug treatment improved visual function coinciding with reduced Caspase-3 mediated retinal cell death. Importantly, all drugs exhibited synergy with vancomycin in improving disease outcomes. Overall, our study identified three non-antibiotic drugs and demonstrated their therapeutic and prophylactic efficacies in ameliorating intraocular bacterial infection.