Designed Antimicrobial Peptides Against Trauma-Related Cutaneous Invasive Fungal Wound Infections

Abstract

Cutaneous invasive fungal wound infections after life-threatening dismounted complex blast injury (DCBI) and natural disasters complicate clinical care. These wounds often require aggressive repeated surgical debridement, can result in amputations and hemipelvectomies and have a 38% mortality rate. Given the substantial morbidity associated with cutaneous fungal wound infections, patients at risk need immediate empiric treatment mandating the use of rapidly acting broad-spectrum antimicrobials, acting on both fungi and bacteria, that are also effective against biofilm and can be administered topically. Designed antimicrobial peptides (dAMPs) are engineered analogues of innate antimicrobial peptides which provide the first line of defense against invading pathogens. The antifungal and antibacterial effect and mammalian cytotoxicity of seven innovative dAMPs, created by iterative structural analog revisions and physicochemical and functional testing were investigated. The dAMPs possess broad-spectrum antifungal activity, in addition to being effective against Gram-negative and Gram-positive bacteria, which is crucial as many wounds are polymicrobial and require immediate empiric treatment. Three of the most potent dAMPs—RP504, RP556 and RP557—possess limited mammalian cytotoxicity following 8 h incubation. If these encouraging broad-spectrum antimicrobial and rapid acting results are translated clinically, these novel dAMPs may become a first line empiric topical treatment for traumatic wound injuries.

A Designed Host Defense Peptide for the Topical Treatment of MRSA-Infected Diabetic Wounds

“…The physiochemical properties of RP557 have been optimized to provide a relationship between net charge, amphipathicity and hydrophobicity that has resulted in decreased proteolytic degradation, broad spectrum antimicrobial (bacteria and fungi) and biofilm inhibition activity with reduced mammalian cytotoxicity, and an increased therapeutic index [10,11,17].…”

“…Designed host defense peptides (dHDPs) are synthetic analogs to naturally occurring antimicrobial peptides (AMPs) found in myeloid and skin resident cells [10]. These peptides have evolved over millennia to mount the first line of defense against invading pathogens, including Gram-positive, Gram-negative bacteria, and fungi [11][12][13][14]. Their amphipathic α-helix or β-sheet structure has a net positive charge that facilitates their insertion into plasma membranes, thus perturbing the barrier function of negatively charged bacterial walls, resulting in rapid bacterial killing even in antibiotic-resistant strains such as MRSA.…”

The potential of functionalized dressing releasing flavonoids facilitates scar-free healing

“…Fungi can quickly invade burns and severely traumatized skin wounds, resulting in widespread wound infections ( 85 ). Fungal cell walls are made up of many layers of carbohydrates such α-mannan and β-glucan ( 86 ).…”