Abstract
Acne vulgaris, caused by the Gram-positive bacterium Cutibacterium acnes, is a prevalent dermatologic condition with substantial cutaneous and psychological morbidity. Mild acne is treated with topical antibiotics with more severe inflammatory forms requiring the prolonged use of oral antibiotics, resulting in antimicrobial resistance development. Innovative treatment alternatives, providing complete microbicidal eradication with minimal safety issues and limited susceptibility to microbial resistance, are fervently sought. Designed antimicrobial peptides (dAMPs) are engineered analogs of naturally occurring AMPs that possess a reduced likelihood of developing bacterial resistance. Seven novel dAMP sequences were screened for in vitro bactericidal effectiveness against antibiotic resistant C. acnes clinical isolates. Five peptides (RP444, RP551, RP554, RP556, and RP557) exhibited potent in vitro antibacterial activity. The Therapeutic Index, a measure of specificity for killing multidrug resistant C. acnes over mammalian cells, was determined using bioluminescent human keratinocytes. The Therapeutic Index was highest for the disulfide dAMP, RP556, with a value of 130. The lead dAMP candidate RP556, was further evaluated in a multidrug-resistant C. acnes intradermal murine infection model. A topical application of 5 mg/mL RP556 (0.5%) eliminated infection. If these preclinical results are translated clinically, dAMPs may become a viable topical monotherapy for the treatment of recalcitrant acne infections.
Highlights
IntroductionAcne vulgaris is a chronic inflammatory skin disorder affecting more than 80% of all adolescents and young adults worldwide [1]
Mild forms of acne are often treated with topical antibiotics, with severe inflammatory forms requiring the prolonged use of oral antibiotics resulting in the development and spread of antimicrobial resistance [4]
Significant antibiotic resistance and multiple drug resistance have observed for C. acnes strains from acne patients following long-term antibiotic treatments [1]
Summary
Acne vulgaris is a chronic inflammatory skin disorder affecting more than 80% of all adolescents and young adults worldwide [1]. The disease can manifest severe social and psychological expressions, including crippling effects on patients’ self-esteem and socialization. The pathogenesis of acne is multifactorial and usually implicates follicular colonization with the Gram-positive Cutibacterium acnes (C. acnes; formerly Propionibacterium acnes), resulting in bacterial overgrowth and inflammation. Current acne treatments present side effects such as erythema, scaling, burning, hair bleaching [2], bacterial resistance, and teratogenic effects [3]. Mild forms of acne are often treated with topical antibiotics, with severe inflammatory forms requiring the prolonged use of oral antibiotics resulting in the development and spread of antimicrobial resistance [4]. Many countries report that more than 50%
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