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Review

Cutibacterium acnes Dysbiosis: Alternative Therapeutics for Clinical Application

by
Sara Sá
1,2,3,
Ruben Fernandes
1,2,4,
Álvaro Gestoso
1,2,
José Mário Macedo
1,2,5,
Daniela Martins-Mendes
1,2,4,
Ana Cláudia Pereira
1,2,4,* and
Pilar Baylina
1,2,6,*
1
FP-BHS—Biomedical and Health Sciences Research Unit, FP-I3ID—Instituto de Investigação, Inovação e Desenvolvimento, FFP—Fundação Fernando Pessoa, 4249-004 Porto, Portugal
2
HE-FP—Hospital Fernando Pessoa, CECLIN—Center of Clinical Studies, 4420-096 Gondomar, Portugal
3
FMUP—Faculty of Medicine, University of Porto, 4420-319 Porto, Portugal
4
FCS—Faculty of Health Sciences, Fernando Pessoa University, 4220-150 Porto, Portugal
5
Faculty of Biology, Department of Functional Biology and Health Sciences, University of Vigo, 36310 Vigo, Spain
6
ESS—School of Health, IPP—Polytechnic Institute of Porto, 4200-072 Porto, Portugal
*
Authors to whom correspondence should be addressed.
Appl. Sci. 2023, 13(21), 12086; https://doi.org/10.3390/app132112086
Submission received: 23 September 2023 / Revised: 29 October 2023 / Accepted: 1 November 2023 / Published: 6 November 2023
(This article belongs to the Section Biomedical Engineering)
Browse Figures
Versions Notes

Abstract

:
Cutibacterium acnes (C. acnes) is a Gram-positive anaerobic facultative bacterium that is part of the human skin commensal microbiome. It colonizes various regions of the body, including the face, back, and chest. While typically a harmless commensal, under certain conditions, C. acnes can become pathogenic, leading to or promoting conditions such as acne vulgaris (AV), post-surgical infections, prostate cancer, and sarcoidosis. Current treatments for C. acnes infections often involve antibiotics, but the rise of antibiotic resistance has raised concerns. This review presents the virulence factors, clinical relevance, and current treatments of C. acnes, highlighting its association with AV, post-surgical infections, and other diseases. It also explores alternative innovative therapies such as phage therapy in development/research that are gaining prominence, with a growing focus on personalized medical approaches. To enhance C. acnes treatment while minimizing side effects and antibiotic prescription concerns, numerous clinical studies have been undertaken. These investigations span various pathological profiles and employ diverse strategies, such as utilizing bacterial extracts and compounds to restore healthy skin flora. The limitations and challenges of current and innovative treatments are also addressed, emphasizing the need for multidisciplinary strategies to combat C. acnes infections effectively.

1. Introduction

1.1. Taxonomy and Nomenclature

C. acnes was firstly described as a member of the Bacillus species and of the Corynebacterium species [1]. Ever since its first isolation, C. acnes has suffered multiple taxonomic reclassifications due to the technological improvements in research and diagnosis, such as proteomic and genomic analysis. In 2016, C. acnes was included in the Propionibacterium genus. However, the known genus was later divided into four genera, namely, Propionibacterium, Cutibacterium, Acidipropionibacterium, and Arachnia. C. acnes was included in the genus Cutibacterium, alongside with Cutibacterium avidum, Cutibacterium granulosum, Cutibacterium namnetense, and Cutibacterium modestum [2]. Nowadays, C. acnes is often described by the following subspecies: acnes (C. acnes type I), defendens (C. acnes type II), and elongatum (C. acnes type III) [2].

1.2. C. acnes Infection and Virulence Factors

Cutibacterium acnes, or C. acnes, was firstly isolated from a patient with chronic acne vulgaris (AV) in the 1900s. It constitutes a healthy human commensal, Gram-positive, and anaerobic facultative bacterium [3]. C. acnes has a broad distribution on the human body, including face, supra, subgingival plaque, back, chest, groin, bend of elbow, intestine, inguinal canal, forearm, palm, plantar heel, and toe, as part of the skin’s microbiota [2,4]. Under normal circumstances, C. acnes does not cause harm and coexists peacefully with other microorganisms. In some situations, however, there can be an overgrowth that can occur when factors like excess sebum production, hormonal changes, or inflammation create conditions favorable for bacterial proliferation. This proliferation permits the formation of biofilms that allow the bacterium to adhere to surfaces, including hair follicles and sebaceous glands on the skin. These biofilms constitute one of several virulence factors that bacteria possess as part of their defense mechanism (Figure 1) [3].
The virulence ability comprises several molecular mechanisms that microorganisms use to infect the host cells and tissues. These virulence factors, summarized in Table 1, are associated with bacterial adhesion and tissue invasion/degradation of the host tissues, allowing the microorganism to overrun the host’s immune system and antibiotic treatments [3].
It is important to note that not all individuals carrying C. acnes will develop this pathogenicity. The transition from commensal to pathogenic depends on various factors, including host genetics, the local microenvironment, and the immune response. The mechanisms underlying these transitions are complex and are an active area of research in dermatology, immunology, and microbiology.

1.3. C. acnes Clinical Relevance

In acne, C. acnes can influence hair follicles, causing them to become plugged with sebum, dead skin cells, and bacteria. This creates an ideal environment for the formation of comedones (blackheads and whiteheads). Virulence factors, such as lipases and proteases, can then exacerbate inflammation and tissue damage, breaking down lipids and proteins, hence contributing to the pathogenesis of acne lesions [3]. In post-surgical infections, C. acnes may enter sterile tissues during surgical procedures through contaminants from the patient’s skin, the air in the operating room, surgical instruments, or even the surgical team [5]. Considering that biofilms can be formed on surgical implants, tissues, or medical devices, the treatment can become a challenge, as the access to the bacteria is limited, due to the biofilm barrier, leading to bacteria proliferation and localized infections [6].
Since C. acnes can metabolize the lipids produced by the human’s sebaceous glands, the density of this bacterium tends to be higher in lipid-rich areas of the human body, such as the face and upper thorax [7]. This distribution is correlated with the risk of infections observed in iatrogenic procedures (post-surgical procedures in shoulders, heart, hip, and others) and to the manifestation of AV. In fact, a study performed on the University affiliated with the Hospital Network in Wisconsin identified 77 patients from post-operative cultures that tested positive for C. acnes: 61% were neurosurgical, 17% orthopedic, 9% cardiothoracic, 8% general surgery, and 5% from other departments [7]. The infections caused by C. acnes were associated with a significant morbidity in these patients and are often underestimated due to the difficulties regarding growth and detection of this bacterium in cultures [6]. Although post-surgery shoulder infections can happen due to several other microorganisms, such as Staphylococcus aureus and Staphylococcus epidermidis, studies regarding post-surgical infections, such as shoulder arthroplasty, detected C. acnes as the main cause in 50 to 60% of the cases [8]. Moreover, infective endocarditis, i.e., the occurrence of an infection on a heart valve and endocardial surfaces, that can lead to a systematic infection, thus raising the risk of patient mortality [9], showed that C. acnes has been responsible for up to 3.5% of the infection endocarditis cases [10].
Due to the capacity of C. acnes to modulate the inflammatory system of the host, it is also often related to sarcoidosis (SC) and prostate cancer [7].
SC is a granulomatous disorder that forms granulomas with Th1 and Th17.1 cells and constitutes a pathological condition that can affect multiple organs, often affecting the lungs and the peripheral lymph nodes. Recently, researchers mentioned the possibility of C. acnes infection being on the list of possible causes for the development of SC in humans, since C. acnes has been detected in tissues affected by SC with high frequency [11].
In prostate cancer, the inflammatory modulation has been related with prostate carcinogenesis [12]. Indeed, it has been described that the presence of C. acnes in patients with prostate cancer correlates to a higher infiltration of regulatory T CD4(+), FoxP3(+) cells in prostatic tissues. Scientists discovered also that this infiltration correlates to the aggressiveness of the prostatic cancer in patients positive for C. acnes [13].

Acne Vulgaris (AV)

AV is a multifactorial disease that affects pilosebaceous units, leading to inflammation and keratinization. AV is developed by the androgen increase in the puberty, consequent increase in the sebum production, and C. acnes colonization in the skin follicle [14]. This colonization leads to the activation of local inflammation and increases the host’s tissue damage [14]. Patients with AV usually begin by presenting comedones (noninflammatory lesions) that may consequently evolve to papules (inflammatory lesions), pustules, nodules, and abscesses, presenting, in severe cases, skin scars [15]. There is not a clear and unique accepted scale for rating acne. However, there are some general tools that can be useful to define or classify the severity of the observed lesions. Two of these tools are the Investigator Global Assessment of acne (IGA) (Table 2), which is accepted by the American Food and Drug Administration (FDA), and the Global Acne Grading System (GAGS) (Table 3), that also takes into consideration the location of the counted lesions [16,17].
Even though there are different phylotypes and subspecies of C. acnes in healthy skin, the phylotype IA1 is the one associated with the lesions observed in AV [18].

1.4. C. acnes Antibiotic Treatment

Antibiotics have been used for more than 40 years to control and promote the elimination of bacterial infections. In clinical practice, there are currently prescribed topical and oral antibiotics to control infections [19].
Topical antibiotics include clindamycin and erythromycin. These drugs work by binding to the 50s ribosomal subunit of the bacteria, disrupting protein synthesis and, ultimately, compromising cell integrity and the replication process. These antibiotics are often used in the treatment of moderate to severe acne, particularly when other topical treatments have been ineffective, and are frequently combined with other active ingredients, such as benzoyl peroxide, to improve therapeutical efficacy [20,21].
Regarding oral treatment, tetracycline antibiotics, such as doxycycline, minocycline, and tetracycline, and macrolide antibiotics, such as erythromycin, are the most commonly used. These antibiotics constitute therapeutics in cases of moderate to severe C. acnes infection and/or when the infection is observed in a larger area of the body. Trimethoprim-Sulfamethoxazole (TMP-SMX) is also prescribed, especially when other antibiotics are ineffective or not well tolerated [22].
However, over the last decade, C. acnes, much like other bacteria, has shown an increase in antibiotic resistance mechanisms, due to its overuse and/or incorrect use, with over 50% of C. acnes strains showing resistance to antibiotic treatments [19]. This alarming increase in bacterial survival created the necessity to search for alternative strategies with similar outcomes regarding treatment efficacy, whether by reducing antibiotic concentration or using alternative compounds. Several studies have been conducted with that goal in mind [23,24,25,26,27]. According to the most recent American recommendation, benzoyl peroxide (BPO) should be used as the first-line treatment for mild to moderate AV, along with a topical retinoid and/or antibiotics [23]. Moreover, other compounds have been considered (Table 4), particularly regarding their use in post-surgery infections as topical antiseptics.

2. New Therapeutic Strategies

To overcome bacterial resistance concerns, there are strategies being explored, not only envisioning therapy efficacy but also a personalized medical approach [28]. Improvements in the treatment of C. acnes rely on the development of novel therapies that maximize efficacy while reducing side effects, as well as issues in public health, such as antibiotics prescriptions. For that, numerous clinical studies have been conducted to understand the outcome of different treatments for C. acnes. Tables S1–S5 (shown in Supplementary Materials) summarize the last decade of such clinical trials associated with this strain’s infection in different pathological profiles, along with summarized methodology and main outcomes in each study.
Since a healthy skin flora can be influenced by exogenous and endogenous factors causing pathological conditions for the host, one of the strategies is the use of bacterial extracts and compounds. This strategy aims to help recover the healthy state of the skin in different pathological conditions such as AV [29]. Ho et al. studied the effects of fermented postbiotics (TYCA06, AP-32 and CP-9 and collagen gel) in the growth inhibition of C. acnes, as well as an in vivo assay on the skin of patients with oily skin and severe AV. The postbiotics displayed a good growth inhibition for C. acnes, and in clinical trials no adverse effects was observed, showing significant reduction in redness, inflammation, and accumulation of porphyrins in skin brown spots. Moreover, there was a significant improvement in the skin hydration and in the AV lesions (in only one week of treatment), even though there was no significant reduction in the sebum skin [30]. Han et al. studied the effects of the E. faecalis CBT SL-5 extract, isolated from healthy Korean human fecal samples in patients with mild to moderate AV. The treatment significantly reduced the phylogenetic diversity in the patient’s skin and was well tolerated by the patients. However, no significant difference was observed in the treatment and in the vehicle lotion in the improvement of AV [31]. Tsai et al. applied a base cream including heat-killed L. plantarum-GMNL6 on one side of the face in 15 females. The treatment significantly reduced the amount of C. acnes and reduced, inclusively, the red areas and the porphyrin [32]. Karoglan et al. performed a microbiome transplantation of beneficial strains of C. acnes to the patient’s skin. The results were not statistically significant but clinical improvements in the noninflammatory lesions were observed. The major limitation of the study was the absence of a control or placebo group and the small participant sample, highlighting the need for further studies with larger groups to correlate the microbiome transplantation with beneficial outcome in AV patients [33].
More recently, phage therapy has been increasingly studied as an innovative approach in bacterial infection treatments.
Phage therapy, short for bacteriophage therapy, is a type of treatment that uses bacteriophages to target and kill specific bacteria (Figure 2). Bacteriophages, often referred to as phages, are viruses that infect and replicate within bacteria, ultimately leading to the bacterial cell’s death [34]. This way, phage therapy constitutes a potential approach for treating bacterial infections, including those caused by bacteria like C. acnes, and involves identifying and isolating specific bacteriophages that can target and infect C. acnes bacteria. Once suitable phages are isolated, they can be purified and used to treat the infection [35]. The phages attach to the surface of C. acnes bacteria, inject their genetic material, and then replicate inside the bacterial cell. This replication ultimately leads to the lysis (bursting) of the bacterial cell, killing it, and releasing more phages to attack other bacteria [35].
Phage therapy entails several advantages, such as (a) specificity, as phages are highly specific to the target bacteria, reducing the risk of harming beneficial bacteria in the body; (b) reduced antibiotic resistance, since phages can be effective against bacteria with multiresistant profile and help overcome virulence mechanisms such as the production of biofilms; and (c) potential for personalized treatment, since it constitutes a therapy that can be tailored to a specific strain that is causing infection [28,34]. This therapy has been considered an optimistic possibility to provide specific treatment in infections with pathogenic bacteria and in dysbiosis conditions when compared to the use of antibiotics [28]. As such, several studies have been conducted, using phages as the vehicle to treat C. acnes bacterial infection.
Xuan et al. recovered isolates of C. acnes, among other strains, from facial abscesses of patients with severe AV. The group succeeded in the isolation of a phage, Y3Z, recovered from the sewage samples, compatible with the strains mentioned, with the ability to perform lysis in all the bacterial isolated from the lesions, showing suitable properties for phage display applications [34].
Kim et al. isolated 15 new C. acnes phages from patients with AV and tested them on clinical isolated strains of C. acnes. The results showed that very few of the pathological strains were susceptible to specific phages in the in vitro assays. However, this was a study that highlighted the benefit of using a cocktail of phages when dealing with multiple strains of pathogenic C. acnes [28].
In another study, Lam and the team isolated a phage from the healthy skin of volunteers that was identified as TCUCAP1. This phage could not only show an efficient lysis effect in in vitro assays with multiresistant clinical isolates of C. acnes, but it also demonstrated a reduction in the inflammatory lesions on mice previously injected with a multidrug-resistant clinical C. acnes isolate (PS023) [36]. Also using a mouse model, Rimon et al. isolated eight phages in their laboratory and C. acnes strains from AV subjects. The group then administered the phages topically to mice previously infected with a virulent clinical C. acnes. The treated mice showed a reduced histological score when compared to the nontreated mice [37].
In a phase 1 cosmetic randomized clinical trial, Golembo and the team aimed to identify and characterize phages targeting C. acnes in subjects with mild to moderate acne. They found broad-spectrum phages, including those targeting antibiotic-resistant strains, with safe and specific genomes. A three-phage cocktail, BX001 was employed in a topical bacteriophage. Results showed reduced C. acnes on the face, aligning with predictions from in silico and ex vivo assessments, suggesting the potential for topically administered phages for acne treatment [38].
An important therapeutic aspect is phages’ temperate nature, allowing coexistence with their host and enabling gene transfer, including antibiotic resistance genes. The safety of phage therapy relies on understanding these dynamics. A study conducted with antibiotic treated mice was found to increase phage integration into bacterial genomes, enriching the phage metagenome with stress-specific functions, shaping the phage–bacterial network. This enrichment also included functions related to host metabolism, such as a broader carbohydrate pathway in ampicillin-treated mice [39]. Such strategies could provide a protective effect in the gut microflora during antibiotic treatments.
Despite all the advantages in this innovative approach, phage therapy also entails some challenges that make its applicability not straight forward.
Identifying and isolating appropriate phages can be challenging and time-consuming, since the affinity towards a specific strain is essential to an effective treatment. Another challenge is the regulatory approval. In many countries, phage therapy is considered experimental, failing to check all the necessary bureaucracies for clinical application and, therefore, not reaching global population. One more challenge, that somewhat correlates with the former, is the lack of clinical data. This limitation constricts the flexibility in terms of phage therapy as a personalized treatment, due to its regulatory limitations that, in the end, result in few clinical trials.

3. Conclusions

Addressing the limitations and concerns associated with current C. acnes treatments requires a multidisciplinary approach involving microbiology, clinical research, and regulatory frameworks. Cutibacterium acnes is a versatile bacterium, with both commensal and pathogenic potential, impacting various aspects of human health. Its association with conditions like acne vulgaris, post-surgical infections, and even prostate cancer underscores its clinical relevance. Current treatments, particularly antibiotic therapy, face challenges such as antibiotic resistance and side effects, among others.
Phage therapy is an area of ongoing research, and its potential for treating various bacterial infections, including those involving C. acnes, is being explored. Some studies have demonstrated that specific phages can effectively reduce C. acnes populations on the skin, potentially offering an alternative or adjunct to antibiotic treatments. However, the effectiveness may vary depending on factors such as the phage cocktail used, the patient’s skin microbiome, and the specific C. acnes strains involved. Such specificity, while providing a challenge, can also been seen as having high potential for personalized medicine. Particularly in microbiome profiling, genetic factors, and host–pathogen interaction, understanding an individual’s skin microbiome can help identify the specific strains of C. acnes present and their interactions with other skin bacteria. This knowledge can guide treatment decisions and the selection of targeted therapies. Genetic factors can influence how a person responds to infections and treatments. Personalized medicine may involve genetic testing to identify genetic variations that affect susceptibility to C. acnes infections or responses to antibiotics or other therapies. Also, understanding how an individual’s immune system interacts with C. acnes can inform treatment strategies. Some people may have immune responses that are more effective at controlling C. acnes, while others may require immune-modulating therapies. Nevertheless, further research and clinical trials are needed to establish the full extent of phage therapy’s effectiveness in treating C. acnes infections and to determine its safety and long-term outcomes. The different studies of phage therapy aim to improve treatment of pathological conditions such as AV, moving towards the decrease in the major pathogenic phylotype of C. acnes while preserving the skin microflora diversity. However, regulatory and clinical data limitations must be addressed for wider application in clinical context.

4. Future Perspectives

The future of C. acnes treatment holds promise in several areas. Microbiome manipulation represents an interesting strategy. In phage therapy, bacteriophages show potential in targeting C. acnes strains with specificity and reducing antibiotic resistance. Moreover, phages’ potential for tailored treatments to individual patients based on their specific C. acnes strains and clinical profiles may improve outcomes and reduce side effects. Further research in clinical trials is needed to establish its efficacy and safety. Hence, conducting more extensive clinical studies and collecting comprehensive data on C. acnes infections will enhance our understanding and treatment options. Moreover, streamlining regulatory processes for innovative therapies such as phage therapy is essential to make these treatments more accessible to patients worldwide. Future developments hold the potential to revolutionize the management of C. acnes-related conditions, ultimately benefiting patients and public health.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/app132112086/s1, Table S1: Brief description of the clinical trials, over the last decade, for Cutibacterium acnes infection in acne vulgaris (AV) treatment. Table S2: Brief description of the clinical trials, over the last decade, for Cutibacterium acnes infection in post-surgery shoulder infections. Table S3: Brief description of the clinical trials, over the last decade, for Cutibacterium acnes infection in other iatrogenic infections. Table S4: Brief description of the clinical trials, over the last decade, for Cutibacterium acnes infection in other skin pathologies. Table S5: Brief description of the clinical trials, over the last decade, for Cutibacterium acnes infection in microbiome studies. References [40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85] are cited in the Supplementary Materials.

Author Contributions

S.S.: Data research, original draft preparation; R.F.: Research, reviewing and editing; Á.G.: Research; J.M.M.: Research; D.M.-M.: Research; A.C.P.: Conceptualization, research, reviewing and editing. P.B.: Conceptualization, research, reviewing and editing. All authors have read and agreed to the published version of the manuscript.

Funding

Pilar Baylina (PB) acknowledges on the behalf of the authors the support of Fundação para a Ciência e Tecnologia (FCT), Portuguese Government, under the Strategic Project Reference: UID/BIM/04293/2013. PB was also supported by FEDER/02/SAICT/2020/072560.

Conflicts of Interest

The authors declare no conflict of interest.

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Figure 1. C. acnes virulence factors allow the bacteria to cause an infection and to survive the host defenses. There are several mechanisms in C. acnes to promote the infection, the evasion of the host defenses, host tissue damage, and invasion, such as a—Lipases can break down sebum and release the free fatty acids, influencing the bacterial capacity to adhere to other cells and surfaces which leads to the formation of comedones; b—Polyunsaturated Fatty Acid Isomerase promotes the catalyzation and the isomerization of linoleic acid; c—Reactive oxygen species (ROS) produced by macrophages (c1) are reduced by C. acnes’ radical oxygenase, inactivating its deadly effects (c2); d—Bacterial biofilms consist of an extracellular matrix composed of proteins, polysaccharides, and/or extracellular DNA. Biofilm production protects C. acnes against the host immune system, most likely by creating a barrier that protects the bacteria from harmful environments such as antibiotics; e—Christ–Atkins–Much–Petersen Factors (CAMP factors) produced by C. acnes (e1) lead to tissue damage by creating membrane pores that promote the lysis of the host cells (e2); f—Hyaluronate lyase promotes the degradation of the host epidermis and dermis extracellular matrix components, such as glycosaminoglycans and hyaluronic acid, allowing the bacterial invasion in the host tissues by the degradation of the skin layers and dissemination of the inflammation; g—Glycosidase enzymes break carbohydrate structures such as host glycolipids and glycoproteins, which permits C. acnes to use host carbohydrates to grow; h—C. acnes’ DsA1 binds to the dermatan sulfate and to fibrinogen protein, involved in the biofilm formation; j—Sialidases remove sialic acid within sialoglyco conjugates, a highly immunogenic protein, although their function in the bacteria pathogenicity is still not clear; l—Sortases F permit the attachment to different proteins, like adhesion factors. These en-zymes are produced in the cytoplasm and promote the transportation of proteins to the bacterial wall.
Figure 1. C. acnes virulence factors allow the bacteria to cause an infection and to survive the host defenses. There are several mechanisms in C. acnes to promote the infection, the evasion of the host defenses, host tissue damage, and invasion, such as a—Lipases can break down sebum and release the free fatty acids, influencing the bacterial capacity to adhere to other cells and surfaces which leads to the formation of comedones; b—Polyunsaturated Fatty Acid Isomerase promotes the catalyzation and the isomerization of linoleic acid; c—Reactive oxygen species (ROS) produced by macrophages (c1) are reduced by C. acnes’ radical oxygenase, inactivating its deadly effects (c2); d—Bacterial biofilms consist of an extracellular matrix composed of proteins, polysaccharides, and/or extracellular DNA. Biofilm production protects C. acnes against the host immune system, most likely by creating a barrier that protects the bacteria from harmful environments such as antibiotics; e—Christ–Atkins–Much–Petersen Factors (CAMP factors) produced by C. acnes (e1) lead to tissue damage by creating membrane pores that promote the lysis of the host cells (e2); f—Hyaluronate lyase promotes the degradation of the host epidermis and dermis extracellular matrix components, such as glycosaminoglycans and hyaluronic acid, allowing the bacterial invasion in the host tissues by the degradation of the skin layers and dissemination of the inflammation; g—Glycosidase enzymes break carbohydrate structures such as host glycolipids and glycoproteins, which permits C. acnes to use host carbohydrates to grow; h—C. acnes’ DsA1 binds to the dermatan sulfate and to fibrinogen protein, involved in the biofilm formation; j—Sialidases remove sialic acid within sialoglyco conjugates, a highly immunogenic protein, although their function in the bacteria pathogenicity is still not clear; l—Sortases F permit the attachment to different proteins, like adhesion factors. These en-zymes are produced in the cytoplasm and promote the transportation of proteins to the bacterial wall.
Applsci 13 12086 g001
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Figure 2. Phage isolation: phages can be collected from water center treatments, hospital facilities, lakes, and human samples. Afterwards, these phages are isolated and tested against different bacterial strains to assess the phages’ antimicrobial potential in specific strains. This specificity promotes a personalized therapy, as it allows it to be applied according to the patient’s specific microbiome. After proper analysis and validation, the phages of interest can be tested for different applications, such as antimicrobial drugs, drug delivery systems, and topical creams, for example.
Figure 2. Phage isolation: phages can be collected from water center treatments, hospital facilities, lakes, and human samples. Afterwards, these phages are isolated and tested against different bacterial strains to assess the phages’ antimicrobial potential in specific strains. This specificity promotes a personalized therapy, as it allows it to be applied according to the patient’s specific microbiome. After proper analysis and validation, the phages of interest can be tested for different applications, such as antimicrobial drugs, drug delivery systems, and topical creams, for example.
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Table 1. C. acnes virulence factors and respective function.
Table 1. C. acnes virulence factors and respective function.
Virulence FactorsFunction
LipasesEnzymes involved in the metabolization of sebum and free fatty acid release and triglycerides.
Polyunsaturated Fatty Acid IsomeraseCatalyzation and isomerization of linoleic acid.
Hyaluronate LyasePromotes the degradation of hyaluronic acid andolaolablablaother glycosaminoglycans, such as chondroitin-4-sulfate, chondroitin-6-sulfate, and dermatan sulfate, of the extracellular matrix in the epidermis and dermis.
GlycosidaseDisruption of carbohydrate and glycan structures that constitute the eukaryotic host glycolipids and glycoproteins.
SialidaseDiscard the sialic acid from sialoglycoconjugates.
Radical oxygenaseReduction of the oxygen free radicals.
Sortase FCapacity to covalently attach to various proteins, including adhesion factors.
PorphyrinFluorescent molecules that can stimulate inflammatory host reactions.
BiofilmMatrix that provides bacterial resistance to adverse compounds, such as antibiotics
Adhesin dermatan-sulfate proteinMolecular surface components that recognize adhesive molecules of the matrix.
Christie–Atkins–Munch–Petersen FactorsPromote the formation of pores in host cells membranes.
Table 2. Investigator Global Assessment of acne (IGA) score, acne severity denomination, and type of lesions observed [17].
Table 2. Investigator Global Assessment of acne (IGA) score, acne severity denomination, and type of lesions observed [17].
ScoreAcne Severity DenominationType of Lesions Observed
0Clear skinNo lesions observed.
1The skin is almost unchangedFew comedones and less, or 1, small inflammatory lesion.
2Mild severity12 comedones and less or equal severe inflammatory lesions.
3Moderate severityMany comedones and more several inflammatory lesions and less, or 1, nodule.
4Severe severityMany comedones and inflammatory lesions, less or equal several nodules and cysts.
Table 3. Global Acne Grading System (GAGS) scale for AV severity rating [16].
Table 3. Global Acne Grading System (GAGS) scale for AV severity rating [16].
Global ScoreLesions Count
None: 0
Mild: 1 to 18
Moderate: 31 to 38
Very severe: >39
Local score = Factor × Grade (0–4)
Factor (1–3)Grade (0–4)
Nose/chin: 1
Forehead/right cheek/left cheek: 2
Chest and upper back: 3		No lesions: 0
One or more comedone: 1
One or more papule: 2
One or more pustule: 3
One or more nodule: 4
Table 4. The positive and negative aspects of compounds used as antiseptics described in clinical studies for Cutibacterium acnes infections in post-surgery contexts [23,24,25,26,27].
Table 4. The positive and negative aspects of compounds used as antiseptics described in clinical studies for Cutibacterium acnes infections in post-surgery contexts [23,24,25,26,27].
CompoundAntibacterial MechanismPositive FactorsNegative Factors
Benzoyl peroxide (BPO)The discharge of reactive oxygen intermediates oxidizes the proteins in the bacterial cell membrane.No bacterial resistance to BPO has emerged despite decades of use. Keratolytic and anti-inflammatory properties are an additional component of BPO.BPO is expensive and is a skin irritant, especially in darker skin types.
ClindamycinInhibits the bacterial 50S ribosome-mediated protein production.Has a synergetic effect when used with BPO. Fox–Fordyce illness, folliculitis, periorificial face dermatitis, and rosacea have all been treated successfully with topical clindamycin, according to reports.C. acnes isolates was shown to be resistant to clindamycin. Topical clindamycin side effects generally take the shape of dryness, stinging, burning, and erythema.
Micozanole Nitrate (MN)Antifungal drug that affects the integrity of fungal cell membranes.Annihilates Malassezia furfur, a fungus that provides an optimal environment for the growth of C. acnes.May provoke allergic reactions, skin irritation such as erythema, pruritus, and occasionally exudation.
Hydrogen Peroxide (HP)Is known by its powerful antiseptic activity against the vast known microorganisms in the skin. It can be used in the concentrations of 3 to 6% of (v/v). Even though the precise mechanism of action of hydrogen peroxide is unknown, it is widely thought that it is connected to its oxidizing activity.No cases of acquired bacterial resistance to HP have been reported. PVP–I and HP interact positively.HP concentrated solutions (20–30% or more) are extremely irritating to the skin and mucous membranes and should be handled carefully.
Chlorhexidine (CHX)CHX has an antibacterial activity by affecting the integrity of cell membranes.Being a highly safe topical medication, chlorhexidine is also commonly found in wound dressings and central line catheters. Chlorhexidine has a broad spectrum of activity and persistent residual effects.Associated with poor efficacy, chlorhexidine side effects are uncommon but include minor skin irritation and, less often, allergic responses such as severe anaphylaxis.
Povidone-iodine (PVP-I)It is hypothesized that PVP–I mechanisms include the inhibition of the electron transportation and cellular and inhibiting protein synthesis.It is considered, among the antiseptics, the one with the broadest spectrum of activity against viruses, bacteria, molds, fungi, yeasts, and protozoa.Low solubility, poor chemical stability, and shows local toxicity if not used in a soluble polymer matrix. PVP–I should not be used in patients with thyroid diseases and applicated iodine radiotherapy and it is also contraindicated to pregnant women or during lactation, and to newborns, and to young children.
IsopropanolIt is hypothesized that alcohols promote the protein denaturation or inhibition of mRNA and protein synthesis.Rapid bacterial activity and broad spectrum of activity (vegetative bacteria, including mycobacteria, viruses, fungi, but not against bacterial spores). No reported allergic reactions.Alcohols’ antimicrobial properties are brief, so they are commonly combined with compounds such as chlorhexidine, which keep working after the alcohol has evaporated.
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Sá, S.; Fernandes, R.; Gestoso, Á.; Macedo, J.M.; Martins-Mendes, D.; Pereira, A.C.; Baylina, P. Cutibacterium acnes Dysbiosis: Alternative Therapeutics for Clinical Application. Appl. Sci. 2023, 13, 12086. https://doi.org/10.3390/app132112086

AMA Style

Sá S, Fernandes R, Gestoso Á, Macedo JM, Martins-Mendes D, Pereira AC, Baylina P. Cutibacterium acnes Dysbiosis: Alternative Therapeutics for Clinical Application. Applied Sciences. 2023; 13(21):12086. https://doi.org/10.3390/app132112086

Chicago/Turabian Style

Sá, Sara, Ruben Fernandes, Álvaro Gestoso, José Mário Macedo, Daniela Martins-Mendes, Ana Cláudia Pereira, and Pilar Baylina. 2023. "Cutibacterium acnes Dysbiosis: Alternative Therapeutics for Clinical Application" Applied Sciences 13, no. 21: 12086. https://doi.org/10.3390/app132112086

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