Development of a topical bacteriophage gel targeting Cutibacterium acnes for acne prone skin and results of a phase 1 cosmetic randomized clinical trial

Abstract

Background Topical antibiotics are frequently used to treat acne vulgaris. Their prolonged use, often for longer durations than recommended, has led to antibiotic resistance in Cutibacterium acnes (C. acnes) , a bacterium implicated in acne pathophysiology. Bacteriophage (phage), which specifically target C. acnes by a different mechanism of action and do not harm potentially beneficial bacteria, may offer an alternative approach for improvement of the appearance of acne prone skin. Objectives To identify and characterize C. acnes targeting phage, carry out a comprehensive preclinical safety evaluation of phages selected for further development and examine their safety, tolerability and ability to target facial C. acnes when applied topically in a cosmetic clinical study including participants with mild‐to‐moderate acne. Methods Phages were isolated by conventional microbiological methods also used to examine their breadth of host range on different C. acnes strains and specificity to this bacterial species. Safety assessment of three selected phages was carried out by complete genomic analysis to assure the absence of undesired sequences and by ex vivo models employed to evaluate the safety, irritability and potential systemic bioavailability of phage applied topically. A randomized, controlled clinical study assessed safety, tolerability and efficacy in targeting facial C. acnes . Results Wide host range phages that also target antibiotic resistant C. acnes were identified. Their genomes were shown to be free of undesired genes. The three‐phage cocktail, BX001, was not irritant to human skin or ocular tissues in ex vivo models and did not permeate through human epidermis. In a cosmetic clinical study, topically applied BX001 was safe and well tolerated and reduced the facial burden of C. acnes . Conclusions Combined in silico and ex vivo approaches successfully predicted the observed safety and efficacy of C. acnes targeting phage when these were topically administered in a well‐controlled cosmetic clinical study.

Whole-genome sequencing, annotation, and biological characterization of a novel Siphoviridae phage against multi-drug resistant Propionibacterium acne

“…In 2018, America reported a case of successful treatment of multidrug-resistant Acinetobacter baumannii infection with phages; In 2022, France reported the treatment of three patients with recurrent Staphylococcus aureus prosthesis knee infection (PKI), in which phage showed good efficacy ( LaVergne et al, 2018 ; Ferry et al, 2022 ). Recently, a phase I clinical trial on topical applied P. acne phages treating antibiotic-resistant acne vulgaris successfully in the United States ( Golembo et al, 2022 ). Besides, our team performed animal experiments demonstrating that phage therapy was as effective as antibiotic therapy.…”

“…Phages can treat bacterial infections regardless of antibiotics-resistance ( Yin et al, 2017 ; Yang et al, 2019a ). There were reports on P. acne phage effectively treating multi-drug-resistant P. acne -induced acne vulgaris in animal experiments ( Lam et al, 2021 ) and clinical trials ( Golembo et al, 2022 ), indicating potential clinical values. However, phage therapy for treating severe acne vulgaris induced by antibiotic-resistant P. acne is insufficient.…”

Myriad applications of bacteriophages beyond phage therapy

“…Currently, the most successful treatment for those patients is a fecal transplant from healthy donors ( Juul et al, 2018 ); however, phages able to kill C. difficile may be another possibility and these have the advantage that they may be used prophylactically in patients with probabilities of develop recurrent diarrhea before or during the antibiotic course ( Hargreaves & Clokie, 2014 ). Furthermore, other dysbioses such as acne, the most common skin infection, is produced by an overgrowth of the bacterium Cutibacterium acnes that triggers inflammatory responses; to date several phages active against C. acnes have been isolated and studied, finding that usually they are able to infect several C. acnes strains which is a good quality for their possible application ( Golembo et al, 2022 ). Another dysbiosis that potentially could be treated with bacteriophages is vaginosis, which is caused by the overgrowth of Gardnerella vaginalis , a natural inhabitant of the female genital tract that is normally non harmful unless it overgrows.…”

The Skin Microbiome: Current Techniques, Challenges, and Future Directions

“…Alternatively, skin bacteriotherapy may also work by, for example, targeting a specific pathogen associated with a dermal condition by using specific metabolites produced by specific bacteria [ 94 ] or through the application of phage therapy. In particular, the use of bacteriophages as a topical therapy has proven to be effective in targeting C. acnes and ameliorating acne [ 96 ]. Phage therapy, however, also comes with its own challenges, particularly those associated with direct and indirect immune responses and arms races, contributing to bacterial and viral evolution, which can ultimately influence the efficiency of phage therapy in skin restoration approaches [ 96 , 97 , 98 ].…”

“…In particular, the use of bacteriophages as a topical therapy has proven to be effective in targeting C. acnes and ameliorating acne [ 96 ]. Phage therapy, however, also comes with its own challenges, particularly those associated with direct and indirect immune responses and arms races, contributing to bacterial and viral evolution, which can ultimately influence the efficiency of phage therapy in skin restoration approaches [ 96 , 97 , 98 ].…”