Acne vulgaris is a multifactorial disease that remains under-explored; up to date it is known that the bacterium Cutibacterium acnes is involved in the disease occurrence, also associated with a microbial dysbiosis. Antibiotics have become a mainstay treatment generating the emergence of antibiotic-resistant bacteria. In addition, there are some reported side effects of alternative treatments, which indicate the need to investigate a different therapeutic approach. Natural products continue to be an excellent option, especially those extracted from actinobacteria, which represent a prominent source of metabolites with a wide range of biological activities, particularly the marine actinobacteria, which have been less studied than their terrestrial counterparts. Therefore, this systematic review aimed to identify and evaluate the potential anti-infective activity of metabolites isolated from marine actinobacteria strains against bacteria related to the development of acne vulgaris disease. It was found that there is a variety of compounds with anti-infective activity against Staphylococcus aureus and Staphylococcus epidermidis, bacteria closely related to acne vulgaris development; nevertheless, there is no report of a compound with antibacterial activity or quorum-sensing inhibition toward C. acnes, which is a surprising result. Since two of the most widely used antibiotics for the treatment of acne targeting C. acnes were obtained from actinobacteria of the genus Streptomyces, this demonstrates a great opportunity to pursue further studies in this field, considering the potential of marine actinobacteria to produce new anti-infective compounds. 2908 antibiot Antibiotics Antibiotics (Basel) Multidisciplinary Digital Publishing Institute (MDPI) PMC9311749 9311749 9311749 35884220 10.3390/antibiotics11070965 Marine Actinobacteria a New Source of Antibacterial Metabolites to Treat Acne Vulgaris Disease—A Systematic Literature Review De La Hoz-Romo Maria Clara 1 2 Díaz Luis 1 2 Villamil Luisa 1 * Monteiro-Neto Valério Academic Editor Fernandes Elizabeth S Academic Editor 1 Doctoral Program of Biosciences, School of Engineering, Universidad de La Sabana, Chía 140013, Colombia; mariaderom@unisabana.edu.co (M.C.D.L.H.-R.); luis.diaz1@unisabana.edu.co (L.D.) 2 Bioprospecting Research Group, School of Engineering, Universidad de La Sabana, Chía 140013, Colombia * Correspondence: luisa.villamil@unisabana.edu.co ; Tel.: +57-313-534-6269 18 7 2022 11 7 965 965 26 7 2022 © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/ ). Abstract Acne vulgaris is a multifactorial disease that remains under-explored; up to date it is known that the bacterium Cutibacterium acnes is involved in the disease occurrence, also associated with a microbial dysbiosis. Antibiotics have become a mainstay treatment generating the emergence of antibiotic-resistant bacteria. In addition, there are some reported side effects of alternative treatments, which indicate the need to investigate a different therapeutic approach. Keywords: biotechnology, marine actinobacteria, antibacterial activity, anti-biofilm activity, quorum-quenching activity, natural compounds, extracts, biosynthetic gene clusters (BGCs), acne vulgaris, Cutibacterium acnes , Staphylococcus aureus , Staphylococcus epidermidis status released display-pdf yes is-olf no is-manuscript no is-preprint no is-journal-matter no is-scanned no is-retracted no Received 2022 Jun 16; Accepted 2022 Jul 13; Collection date 2022 Jul. 1. Introduction Acne vulgaris is an inflammatory disease of the pilosebaceous unit that includes the hair follicle, hair shaft, and sebaceous gland. Currently, all treatments available for the management of acne, topical or systemic, generate Despite this, it is considered to have low antibacterial activity against diverse types of pathogens (both Gram-positive and Gram-negative bacteria) [ 138 ]. Likewise, it was found that butenolide not only effectively inhibited the biofilm formation but also eradicated pre-formed biofilms of tested bacteria and it also had a synergistic effect with tetracycline; it was a potential tetracycline enhancer against biofilm-associated infection-producing bacteria such as E. coli, P. aeruginosa , and MRSA [ 138 ]. Another compound with antibacterial, antibiofilm, and QQ activity is a melanin pigment. Out of these Actinobacteria, Streptomyces is the genera known as the most prolific, with many natural products with antibacterial, antifungal, antioxidant, antitumor activity, etc., from which products have been developed with a wide range of pharmaceutical applications contributing to a high number of antibiotics with current pharmaceutical applications, potentially useful to treat acne vulgaris [ 101 ]. acnes is an anaerobe could increase the technical requirements to carry out the antibacterial activity screening; nevertheless, it is highly expected that the antibacterial compounds here described also have antibacterial activity against this bacterium. It is important to point out that two of the antibiotics most currently used to treat acne were obtained from actinobacteria of the Streptomyces genus from soil samples. Search Strategy A systematic search was conducted in PubMed, Scopus, and Web of Science (WOS) without limits of timeframe (The first search was in May 2021 and the last updated in April 2022). The search strategy for all databases included the descriptors: “streptomyces”, “actino”, “acne”, “antibacterial”, “quorum quenching” and other terms combined with Boolean operators AND and OR and it defined as follows. ((streptomyces OR action *) AND (acne * OR “staphylococcus epidermidis” OR “staphylococcus aureus” OR “cutibacterium acnes” OR “propionibacterium acnes”) AND (antibacterial OR quorum OR “quorum quenching”)).

Background Cutibacterium acnes ( C. acnes ) is closely related to the pathogenesis of acne, and studies related to the antibiotic resistance rates of C. acnes have been reported worldwide; however, relevant systematic reviews and meta-analyses are still lacking. The aim of this study was to systematically evaluate the resistance in C. acnes to relevant antibiotics, that this information may be used to provide a rational basis for the antibiotic treatment of acne. Methods Relevant studies in PubMed, the Cochrane Library, EMBASE, Web of Science, China National Knowledge Infrastructure (CNKI) and Wanfang Data were systematically searched from January 1, 2005, to April 1, 2025, and the resistance rates of C. acnes isolates to quinolones, macrolides, tetracyclines, and other relevant antibiotics were collected. The combined resistance rate was calculated via the R language program package 4.3.2, with subgroup analyses based on different years, continents, countries, provinces in China and different drug susceptibility testing methods. Results A total of 8,846 studies were systematically retrieved and 23 studies were included, corresponding to 2,046 isolates of C. acnes , which have shown antibiotic resistance rates ranging from high to low: 48.17% (95% CI: 41.16–55.24%) for roxithromycin, 45.64% (95% CI: 20.49–73.22%) for clarithromycin, 43.33% (95% CI: 27.81–60.29%) for azithromycin, 29.20% (95% CI: 22.14–37.43%) for erythromycin, 22.38% (95% CI: 14.69–32.56%) for clindamycin, 5.93% (95% CI: 2.91–11.69%) for levofloxacin, 2.44% (95% CI: 0.99–5.89%) for doxycycline, 1.47% (95% CI: 0.00–85.72%) for trimethoprim-sulfamethoxazole (TMP–SMX), 1.31% (95% CI: 0.45–3.70%) for tetracycline, 0.28% (95% CI: 0.04–1.94%) for chloramphenicol, 0.22% (95% CI: 0.03–1.89%) for minocycline. Subgroup analysis revealed that, compared with those in other regions, the resistance rates to macrolides and clindamycin were higher in China. In addition, the levofloxacin, erythromycin, and clindamycin resistance rates were progressively increasing over time. Conclusion In certain regions, the relatively high antibiotic resistance rates (e.g., 77% (95% CI: 62–87%) for clarithromycin in China) in C. acnes isolates may be attributed to the overuse of antibiotics in acne treatment. The resistance rates in C. acnes to tetracyclines, such as 2.44% (95% CI: 0.99–5.89%) for doxycycline, remain relatively low, which allows tetracyclines to continue serving as first-line antibiotics for acne treatment. In addition, the resistance rates to levofloxacin, erythromycin, and clindamycin markedly increased over time ( p < 0.05). This emphasizes the significance of rational use of the antibiotics in acne treatment.

<h4>Objective</h4>This study aimed to assess the overall antibiotic susceptibility of Cutibacterium acnes (C. acnes), a bacterium implicated in acne vulgaris, with a particular focus on clindamycin and fluoroquinolones, which are commonly used in inflammatory acne treatment.<h4>Methods</h4>A systematic search of Scopus, PubMed, Web of Science and EMBASE databases was conducted to identify relevant studies. Pooled prevalence estimates were calculated using a random-effects model, and additional analyses included quality assessment, evaluation of publication bias, meta-regression and subgroup analyses based on antimicrobial susceptibility methods and year of publication.<h4>Results</h4>The analysis incorporated a total of 39 studies. The random-effects model revealed that the proportion of clindamycin-resistant isolates was 0.031 (95% CI: 0.014-0.071). Additionally, macrolides, including erythromycin (0.366; 95% CI: 0.302-0.434) and azithromycin (0.149; 95% CI: 0.061-0.322), exhibited distinct prevalence rates. Tetracyclines, including doxycycline (0.079; 95% CI: 0.014-0.071), tetracycline (0.062; 95% CI: 0.036-0.107) and minocycline (0.025; 95% CI: 0.012-0.051), displayed varying prevalence estimates. Fluoroquinolones, including ciprofloxacin (0.050; 95% CI: 0.017-0.140) and levofloxacin (0.061; 95% CI: 0.015-0.217), demonstrated unique prevalence rates. Additionally, the prevalence of the combination antibiotic trimethoprim/sulfamethoxazole (SXT) was estimated to be 0.087 (95% CI: 0.033-0.208).<h4>Conclusion</h4>The study findings highlight a concerning increase in antimicrobial-resistant C. acnes with the use of antibiotics in acne treatment. The strategic utilization of appropriate antimicrobials has emerged as a crucial measure to mitigate the emergence of antimicrobial-resistant skin bacteria in acne management.

Background Cutibacterium acnes (C. acnes) is a causative agent in the development of acne vulgaris, and this bacteria has been reported to show resistance against conventional antibiotics. One of the vital factors contributing to antibiotic resistance is the ability of C. acnes to form biofilms. Thus, the purpose of this review is to assess the efficacy of various recent developments and to identify acceptable methods for preventing infections associated with C. acnes biofilms. Methodology A variety of criteria considered in the selection process, such as the site of infection, the mechanism of action against biofilms, and the methodology used to evaluate antibiofilm activity, were taken into consideration when choosing the studies. Results The findings of existing research on the antibiofilm potential of conventional anibiotics, natural products and novel treatment strategies against C. acnes were compiled and compared. Clinical trials demonstrated that dalbavancin reduced biofilm formation while niosomes effectively decreased inflammation in acne lesions. Some studies have shown promising results with bacteriophages, plant-based and nanomaterial treatments, but lack further validation in the way of pre-clinical and clinical trials to accurately measure treatment effectiveness. Conclusions The review examines a range of effective agents and explores their potential applications in acne management, offering valuable insights for clinicians—especially dermatologists—seeking to optimize patient care. In addition, this review provides an understanding about the different agents and their antibiofilm properties that enable researchers to develop effective therapeutic approaches against C. acnes biofilm-related infectious diseases for the benefit of human health. 2026 Karar et al. https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ) and either DOI or URL of the article must be cited. Background Cutibacterium acnes (C. acnes) is a causative agent in the development of acne vulgaris, and this bacteria has been reported to show resistance against conventional antibiotics. Conclusions The review examines a range of effective agents and explores their potential applications in acne management, offering valuable insights for clinicians—especially dermatologists—seeking to optimize patient care. In addition, this review provides an understanding about the different agents and their antibiofilm properties that enable researchers to develop effective therapeutic approaches against C. acnes biofilm-related infectious diseases for the benefit of human health. Cutibacterium acnes Biofilm formation Therapeutic agents Antibiotic resistance Human health The authors received no funding for this work. One important aspect of C. acnes’ pathogenicity is its ability to develop biofilms. Biofilms aid in the development of resistance towards antibiotics, which make infections challenging to treat using these therapeutic agents. In addition, biofilms shield the bacteria from environmental stress and the host immune system, this increasing the survival of these pathogens ( Mayslich, Grange & Dupin, 2021 ). Due to these reasons, it is vital to Inclusion Criteria • Papers on Cutibacterium acnes published in SCOPUS or WoS journals within the past 10 years • Papers that included information about taxonomy, cell wall composition, antibiotic resistance, biofilm development, anti-biofilm activity, etc. Exclusion Criteria • Papers including information solely belonging to other genera of Gram negative bacteria. • Papers published in non-SCOPUS journals. C. acnes Biofilms and Related Infections in Implant-Associated Devices The ability of C. acnes to form biofilms was first described by Tunney et al. (1999) , who found this on prosthetic hip implants. Subsequent studies demonstrated that biofilm formation by C. Additionally, developing sophisticated animal models and ex vivo systems that closely mimic human skin and implant environments can provide more physiologically relevant platforms for testing therapeutic interventions. In addition, despite the major advances in therapeutic options, the treatment of biofilm-related infections is further complicated by the increase in antibiotic-resistance among the biofilm-forming C. acnes isolates. Antimicrobial Resistance in C. acnes The first antibiotic resistance case in acne was observed in the 1970s and involved C. acnes isolates ( Pannu et al., 2011 ). acnes can prevent biofilm formation or promote biofilm dispersal. Enzymes that degrade extra polymeric substances (EPS) components within the biofilm or molecules that inhibit quorum sensing are potential candidates in these strategies ( Sikdar & Elias, 2020 ). Using combined antibiotics like rifampin with β-lactams or clindamycin, and combinations of antibiotics with calcium sulfate, or with povidone-iodine have been shown to successfully treat periprosthetic joint infections caused by biofilm-associated C. acnes ( Kusejko et al., 2021 ). Since this isolate was obtained from human saliva, this in vitro study highlighted the potential of using this bacteriophage to treat persistent C. acnes infections in dental implants where conventional antibiotics fail. The potential therapeutic benefits of the groups of natural agents based on effectiveness, safety and scalability has been summarized in Table 4 . Overall, bacteriophages have the greatest therapeutic potential due to its superior effectiveness and specificity, despite moderate scalability challenges. Bacterial compounds and biosurfactants, on the other hand, offer a good balance of safety, effectiveness and scalability, which is more ideal commercially.

Cutibacterium acnes plays a key role in the development of acne vulgaris, with biofilm formation contributing to its persistence and resistance to antimicrobial treatments. A critical component of C. acnes biofilms is poly-N-acetylglucosamine (PNAG), an exopolysaccharide that facilitates both biofilm stability and biocide resistance. This study evaluated the efficacy of the PNAG-degrading enzyme dispersin B in enhancing the susceptibility of C. acnes biofilms to benzoyl peroxide (BP), a common anti-acne agent. Dual-species biofilms of C. acnes and Staphylococcus epidermidis, which has been shown to promote C. acnes biofilm growth under aerobic conditions, were cultivated in glass tubes and treated with dispersin B (5–80 µg/mL), BP (0.1–2.5%), or a combination of both. Dispersin B or BP alone reduced C. acnes colony-forming units (CFUs) by 1–2 log units. However, sequential treatment with dispersin B followed by BP achieved a synergistic effect, yielding a >6-log reduction in CFUs. Remarkably, concentrations as low as 5 µg/mL dispersin B combined with 0.5% BP efficiently eradicated C. acnes from the dual-species biofilms. These findings highlight the protective role of PNAG against BP and demonstrate the potential of dispersin B as an adjunctive therapy to enhance the efficacy of BP in acne treatment.

Acne vulgaris is a chronic inflammatory skin condition with a multifactorial pathogenesis involving follicular hyperkeratinization, sebaceous gland dysregulation, microbial dysbiosis-particularly involving Cutibacterium acnes and Staphylococcus epidermidis-and complex immune-mediated mechanisms, on which T helper cell 1 (T_h1) and T_h17 pathways are central players. This evolving understanding has led to the exploration of biologic therapies targeting cytokines such as tumor necrosis factor-alpha (TNFα), interleukin (IL)-1, IL-17, and IL-23. However, clinical trials to date have not demonstrated efficacy of biologics in moderate to severe acne. In contrast, some case reports and studies suggest clinical improvement with TNFα and IL-17A inhibitors in severe, treatment-resistant acne, although these presentations often overlap with hidradenitis suppurativa (HS), raising questions about diagnosis and underlying disease mechanisms. Furthermore, in various monogenic autoinflammatory syndromes where "acne-like" lesions are part of the clinical spectrum, biologic therapies have shown effectiveness. These observations suggest that in such contexts, the lesions may reflect HS or HS-like pathology rather than true acne, potentially explaining the therapeutic benefit of biologicals in this context. This review synthesizes current insights into the immunopathogenesis of acne and critically evaluates the rationale, evidence, and limitations of biologic therapy in its treatment. While biologics hold promise in defined inflammatory dermatoses, their role in the management of acne vulgaris remains unproven and may be limited to specific phenotypes that overlap with autoinflammatory or HS-related conditions.

Resistance of Cutibacterium acnes to topical antibiotics historically used to treat acne (topical erythromycin and clindamycin and, more recently, topical azithromycin and clarithromycin) has been steadily increasing and new topical antibiotics are needed. Minocycline is a semisynthetic tetracycline-derived antibiotic currently used systemically to treat a wide range of infections caused by Gram-negative and Gram-positive bacteria. In addition to its antibiotic activity, minocycline possesses anti-inflammatory properties, such as the downregulation of proinflammatory cytokine production, suppression of neutrophil chemotaxis, activation of superoxide dismutase, and inhibition of phagocytosis, among others. These characteristics make minocycline a valuable agent for treatment of dermatological diseases such as acne vulgaris and papulopustular rosacea. However, more frequent or serious adverse effects have been observed upon the systemic administration of minocycline than with other tetracyclines. Examples of serious adverse effects include hypersensitivity syndrome reaction, drug-induced lupus, idiopathic intracranial hypertension, and other autoimmune syndromes that may cause death. Here, we review adverse effects and drug–drug interactions observed with oral administration of minocycline and contrast this with topical minocycline formulations recently approved or under development for effectively treating dermatological disorders with fewer adverse effects and less drug inter Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/ ). Abstract Resistance of Cutibacterium acnes to topical antibiotics historically used to treat acne (topical erythromycin and clindamycin and, more recently, topical azithromycin and clarithromycin) has been steadily increasing and new topical antibiotics are needed. Minocycline is a semisynthetic tetracycline-derived antibiotic currently used systemically to treat a wide range of infections caused by Gram-negative and Gram-positive bacteria. Many strains of Gram-positive bacteria are resistant to tetracyclines; thus, culture and susceptibility tests are recommended prior to use. As a broad-spectrum antibiotic, minocycline is used to treat many bacterial infections, such as urinary tract infections, respiratory infections, skin infections (such as moderate-to-severe acne), chlamydia, tick fever, and others. It is also used for gonorrhea, syphilis, and other infections as a second-line drug in patients with allergy to penicillin [ 9 ]. acnes ) , alteration of follicular hyperkeratinization, altered sebum production under androgen control, complex inflammatory mechanisms involving innate and adaptive immune systems, and neuroendocrine regulatory mechanisms [ 20 , 21 ]. Like rosacea, acne negatively impacts patient quality of life leading to low self-esteem, depression, and social isolation [ 22 ]. 2.2. Antibiotic Resistance to Topical Macrolide Antibiotics Historically Used to Treat Acne Topical clindamycin, erythromycin, azithromycin, and clarithromycin have been used globally to treat acne [ 23 ]. However, evidence indicates that antibiotic resistance of C. Oral and IV formulations are used to treat infections by microorganisms sensitive to minocycline [ 31 ]. Table 1 Brands of minocycline currently approved for systemic use in the USA market [ 8 , 9 , 32 ]. Brand Dosage Forms Manufacturer Indications Cleeravue-M Oral tablets, extended release StoneBridge Pharma Moderate-to-severe acne vulgaris. Dynacin Oral capsule Medicis, The Dermatology Co.; Par Pharmaceutical, Inc. Adverse Effects of Oral Minocycline The most common concern of long-term systemic minocycline use for acne is the development of resistant microorganisms. Minocycline has a lower rate of C. acnes resistance compared to tetracycline and doxycycline [ 27 ], and C. acnes strains exhibited similar spontaneous mutational frequencies when comparing sarecycline, vancomycin, and minocycline [ 4 ]. Gastrointestinal dysbiosis, or disruption of the normal gut microbiome homeostasis, is also a concern of long-term use of broad-spectrum oral antibiotics. While some authors report a benign condition, which disappears spontaneously upon interruption of the offending agent, others report more severe cases involving permanent vision loss [ 58 ]. Fraser et al. [ 59 ] reported a rapid onset case of IIH in a 12-year-old girl being treated with oral minocycline for acne vulgaris, which led to permanent vision loss despite minocycline interruption and interventions such as a lumbar puncture Topically applied minocycline also carries the advantage of avoiding the many possible side effects and interactions associated with the systemic use of the antibiotic. 5.3. Pharmacokinetics of Topical Minocycline The pharmacokinetics of topical minocycline differ from systemic minocycline [ 130 , 148 ]. Jones et al. [ 148 ] reported a study with 30 adults with moderate-to-severe acne comparing the systemic effects of single-dose oral administration (1 mg/kg) of extended-release Solodyn ® capsules, with a multidose (total of 4 g) topical administration of 4% minocycline hydrochloride. Conclusions Tetracyclines, especially minocycline and doxycycline, have historically been the most commonly prescribed oral antibiotics to treat dermatological conditions such as acne and rosacea. However, there are several adverse effects associated with oral administration of these second-generation tetracyclines, which, especially in the case of minocycline, may be severe. Although rare, some of the side effects may be fatal. These serious effects led the Drug Therapy Bulletin to publish an editorial entitled “Time to say goodbye to minocycline?” [ 155 ] which states that there is no clinical advantage that justifies the prescription of oral minocycline for treating acne [ 43 ].

Topical Metformin Emulgel VS Salicylic Acid Peeling in Treatment of Acne Vulgaris Acne Vulgaris (AV ) is a common skin disorder worldwide, affecting all ages and races, considered as a long term chronic inflammatory disease of the skin.It affects nearly 85% of adolescents and about 30% of adults which is known as post- adolescent acne that often occurs in individuals aged 25 years or older particularly women. Acne lesions, which may be papules, pustules, or nodules commonly affecting face, chest and back therefore acne patients may suffer from emotional distress due to its chronicity and potential outcomes which include physical scars and persistent hyperpigmentation. The pathophysiology of AV involves four factors: abnormal follicular keratinization, hyperseborrhea, Cutibacterium acnes proliferation in the pilosebaceous unit and inflammatory mediators released into the skin. Diet is considered to be one of the main factors influencing the induction and aggravation of acne, though this is still debatable.