Propranolol demonstrates antifungal activity against Fusarium and Apergillus corneal isolates and in a murine model of fungal keratitis.

Abstract

Purpose : Fungal keratitis (FK) is an infection of the cornea that frequently results in the need for corneal transplantation even with prompt topical ocular antifungal therapy. Natamycin remains the only FDA-approved drug for FK, but prompt sterilization of the cornea is often not attained. Recently, natamycin synergy with the beta-adrenergic antagonist timolol against Fusarium species was reported. In this study we characterize the in vitro antifungal effects of additional beta-adrenergic antagonists against FK-relevant molds and explore their effects in a murine model of FK.

Methods : Microbroth dilution assays were used to determine the minimal inhibitory concentration (MIC) of beta-adrenergic antagonists against 18 Fusarium spp. isolates (10 from the Mycotic Ulcer Treatment Trial, 8 from USA) and 3 Aspergillus fumigatus isolates. The fractional inhibitory concentration index (FICI) was calculated to assess interactions with natamycin. A corneal abrasion model followed by inoculation was used to create fungal corneal infections in mice. C57BL/6J corneas were inoculated with A. fumigatus and treated with propranolol both topically (0.1% drops; 3X daily starting on day 0) and via intraperitoneal injection (2 mg/kg; 1x daily starting on day -1). Sham-treated animals received topical and i.p. PBS (n=10/group).

Results : Most beta-blockers did not show antifungal activity or synergy with natamycin with the exception of propranolol. A racemic mix of propranolol had fungicidal activity with MIC between 31 and 83 μg/mL for the Fusarium isolates. The MIC of the less cardioactive R enantiomer was lower (27-83 μg/mL) than the MIC of the S enantiomer (42-104 μg/mL). The MICs of both propranolol and natamycin were lower in combination but were not synergistic. The MIC of propranolol was 156 μg/mL for the A. fumigatus isolates. In a murine model of Aspergillus FK, viable fungus was not recovered in any of propranolol treated animals after at 72 hours post-inoculation and clinical grading was mild compared to saline treated controls

Conclusions : These data suggest that propranolol has antifungal activity against the two predominant FK pathogens, Fusarium and Aspergillus, and that it may have a role in the treatment of FK.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.