Alternative Therapeutic Interventions: Antimicrobial Peptides and Small Molecules to Treat Microbial Keratitis

Abstract

Microbial keratitis is a leading cause of blindness worldwide and results in unilateral vision loss in an estimated 2 million people per year. Bacteria and fungus are two main etiological agents that cause corneal ulcers. Although antibiotics and antifungals are commonly used to treat corneal infections, a clear trend with increasing resistance to these antimicrobials is emerging at rapid pace. Extensive research has been carried out to determine alternative therapeutic interventions, and antimicrobial peptides (AMPs) are increasingly recognized for their clinical potential in treating infections. Small molecules targeted against virulence factors of the pathogens and natural compounds are also explored to meet the challenges and growing demand for therapeutic agents. Here we review the potential of AMPs, small molecules, and natural compounds as alternative therapeutic interventions for the treatment of corneal infections to combat antimicrobial resistance. Additionally, we have also discussed about the different formats of drug delivery systems for optimal administration of drugs to treat microbial keratitis.

Keywords: antimicrobial pepides; drug delivery systems; microbial keratitis; ocular surface; small molecules; wound healing.

FIGURE 1

Representative images of microbial keratitis. The pathogens causing infections penetrates deep into the stroma inducing inflammation and corneal opacity that leads to loss of vision.

FIGURE 2

A schematic representation of AMPs expressed in eye. The expression of several AMPs in the anterior part of the eye including tears, conjunctiva, iris, lens, aqueous humor, and corneal epithelium. The corneal epithelial cells express several AMPs constitutively or in response to pathogen attack and wound healing.

FIGURE 3

LL-37 expression in corneal tissues obtained from S. pneumoniae keratitis patients. Corneal sections of keratitis patients obtained during corneal transplantation and control cadaveric corneas were stained with anti-LL-37 antibody, followed by Alexafluor 488 secondary antibody and imaged under a fluorescent microscope using 10X objective. The sections were counterstained with DAPI. E denotes epithelium, S-stroma, and En-endothelium. This figure is reprinted from reference Sharma et al. (2019).

FIGURE 4

Representative structures of AMPs. Structures of LL-37 (Wang, 2008) (A), hBD-2 (Hoover et al., 2000) (B), and crystal structure of human calprotectin (S100A8/S100A9) (Korndorfer et al., 2007) (C).

FIGURE 5

Representative structures of small molecules. 2-Imino-5-Arylidene thiazolidinone (Felise et al., 2008) (A), INP0341 (Nordfelth et al., 2005) (B), 2-mercaptoacetyl-L-phenylalanyl-l-leucine (Kessler et al., 1982) (C), Targocil (Farha et al., 2015) (D), Pseudolipasin A (Lee et al., 2007) (E), Glycyrrhizin (Ji et al., 2016) (F), Simvastatin (Jensen et al., 2016) (G), Suberoylanilide hydroxamic acid (Choi and Pflum, 2012) (H), and Atovaquone (Nixon et al., 2013) (I).