NEW SMALL MOLECULES AND PROCESSES USING THEM FOR SKIN TREATMENT

Abstract

NEW SMALL MOLECULES AND METHODS USING THEM FOR SKIN TREATMENT. The disclosure relates to new biosynthetic gene clusters encoding type II polyketides, their products, extracts and compositions comprising the products, and methods for using the products, extracts, and compositions for skin treatment, e.g., to enhance the skin's barrier function and / or immune defenses. Figure for abstract: none

Description

Title of the invention: NEW SMALL MOLECULES AND METHODS USING THEM FOR SKIN TREATMENT technical field

[0001] This disclosure relates to small molecules, extracts and compositions comprising the molecules, and processes using them for skin treatment, for example to strengthen the skin's barrier function and / or immune defenses. CONTEXT

[0002] The skin, which is the largest organ of the human body, is colonized by beneficial microorganisms, and together they serve as a barrier to prevent the invasion of pathogens. Under circumstances where the barrier is breached, or when the balance between commensal bacteria and pathogens is disrupted, skin diseases or disorders may occur.

[0003] The human skin microbiome comprises a thousand species of bacteria, at least some of which can disrupt or promote skin health. For example, it has been shown that people with atopic dermatitis have an altered skin bacterial flora compared to people without atopic dermatitis, with the skin of people with atopic dermatitis being dominated by higher proportions of Staphylococcus aureus compared to those with healthy skin. Conversely, at least some commensal bacteria are thought to play a role in protecting the skin against external aggressions and pathogens. The metabolites produced by these bacteria can, in some cases, inhibit pathogenic microbes and, in other cases, promote beneficial ones, thus rebalancing the microbiome of the altered skin.As an example, Staphylococcus epidermidis is thought to increase skin ceramide levels and improve skin hydration through the secretion of sphingomyelinase.

[0004] Coagulase-negative staphylococci (CNS) constitute a heterogeneous group of bacteria that are less frequently associated with human infections than species possessing a broad range of virulence factors, such as S. aureus. For example, one CNS strain, Staphylococcus saccharolyticus, is part of the skin microbiota and rarely causes human infections. S. saccharolyticus requires more delicate growth conditions than other CNS strains and has only recently been accurately identified. However, S. saccharolyticus has been the subject of little research to date. Another example The most common coagulase-negative staphylococcus (CNS) in the skin microbiota is Staphylococcus warnei. Although they are considered predominant agents of skin colonization, the role of S. saccharolyticcus and S. wamei in skin homeostasis and skin health has been relatively poorly characterized.

[0005] It therefore remains necessary to know more about the function of the skin microbiome and its role in skin health.

[0006] In addition to the need for options to treat and / or prevent skin diseases and disorders, many consumers engage in routine or preventative skincare to improve the overall appearance or health of their skin, and / or to treat specific skin problems. For example, consumers seek cosmetic skincare products that temporarily or permanently delay or eliminate signs of aging, counteract negative environmental influences, prevent dehydration, etc.

[0007] Furthermore, the formulation of environmentally friendly cosmetic products, designed and developed with environmental considerations in mind, is becoming a major objective in the effort to address global challenges. It is therefore essential to offer more sustainable compositions, preparation processes, and ingredients to meet these environmental concerns. In this context, it is important to develop new cosmetic products and processes with a lower carbon footprint, particularly by promoting the use of renewable raw materials and / or cosmetic compositions with a high naturalness index and / or materials of natural origin, and, more specifically, by reducing the use of petrochemical-derived compounds.

[0008] Consequently, there is a continuing need to improve skin care and products. It has now been discovered, surprisingly and serendipitously, that compositions comprising a purified fraction of bacteria enriched with a new range of polycyclic aromatic polyketides can improve skin health and appearance. SUMMARY

[0009] The disclosure relates to novel biosynthetic gene clusters that code for type II polyketides, as well as products thereof, extracts and compositions comprising the products, and processes for treating the skin with the products, for example, to enhance or strengthen the skin barrier function, improve the skin's immune defenses, and / or treat various types of skin diseases or conditions.

[0010] The disclosure also relates to a range of new polycyclic aromatic polyketides (“Compound Range 1”), extracts and compositions comprising the molecules, and processes for treating skin with the molecules, for example to improve or strengthen the skin's barrier function, enhance the skin's immune defenses, and / or treat various types of skin diseases or conditions.

[0011] The disclosure further relates to extracts of S. saccharolyticcus bacteria, for example bacterial extracts derived from skin, compositions comprising bacterial extracts, and processes for treating skin with bacterial extracts and / or compositions, for example to improve or strengthen the skin barrier function, strengthen the skin's immune defenses, and / or treat various types of skin diseases or conditions.

[0012] The disclosure also relates to extracts of S. warnei bacteria, for example bacterial extracts derived from skin, compositions comprising bacterial extracts, and processes for treating skin with bacterial extracts and / or compositions, for example to improve or strengthen the skin barrier function, enhance the skin's immune defenses, and / or treat various types of skin diseases or conditions.

[0013] In some embodiments, the skin treatment processes are processes intended to strengthen the skin's barrier function. In other embodiments, the skin treatment processes are processes intended to strengthen the skin's immune defenses. In still other embodiments, the skin treatment processes are processes for treating a skin disease, condition, or disorder. For example, the processes may be processes for treating atopic dermatitis.

[0014] The products of the new biosynthetic gene clusters encoding type II polyketides, including molecules from Compound Range 1, extracts of the bacterium S. saccharolyticcus, and extracts of the bacterium S. warnei, can also be used as biomarkers. Thus, the disclosure further relates to methods for detecting skin diseases, disorders, or conditions, for example, atopic dermatitis. BRIEF DESCRIPTION OF THE FIGURES

[0015] [Fig.1] Fig.1 shows the genetic organization of TILPKS BGC5 in S. saccharolyticcus and S. warnei.

[0016] [Fig.2] [Fig.2] shows the UV absorbance of the S. saccharolyticcus fractions purified. HPLC peaks that absorb at 400 nm can only be observed in cell extracts from cultures grown in TSB.

[0017] [Fig 3A-3C] The [Fig.3A] -3C show UV (3A), NMR (3B) and mass spectrometry (3C) data characterizing a new molecule from Compound Range 1.

[0018] [Fig 4A-4B] The [Fig.4A] -4B show graded results of upregulation of genes associated with skin barrier function (FLG, IVL and LOR), and of genes associated with cell differentiation (CLDN1, TGM1, KRT16 and KRT6A) in primary keratinocytes from healthy donors and / or in the same keratinocytes treated with S. aureus.

[0019] [Fig 5A-5B] The [Fig.5A] -5B show graded results of an increase in the expression of antimicrobial peptides and innate immune genes involved in immune defenses (S100A7, RNASE7, DEFB4A and PI3) in primary keratinocytes from healthy donors and / or in the same keratinocytes treated with S. aureus. DETAILED DESCRIPTION

[0020] The disclosure relates to novel biosynthetic gene clusters encoding type II polyketides, products thereof comprising a range of novel molecules, bacterial extracts containing the products and / or molecules, compositions comprising the products and / or molecules, compositions comprising the bacterial extracts, and skin treatment processes. The products and / or molecules may also be used as biomarkers to detect skin diseases. MOLECULES, EXTRACTS AND COMPOSITIONS

[0021] In various embodiments, the disclosure relates to bacterial extracts. In particular, the disclosure relates to extracts of the bacteria S. saccharolyticcus and S. wamei, for example, bacterial extracts derived from skin. The extracts are preferably purified. In other embodiments, the disclosure relates to products in the extracts, for example, products of biosynthetic gene clusters (“BGCs”) that encode type II polyketides (“TILPKs”).

[0022] Polyketides are secondary metabolites that exhibit diverse chemical structures and a wide variety of biological activities, for example, antibacterial, antifungal, anticancer, antiviral, immunosuppressive, anticholesterolemic, and anti-inflammatory activity. Polyketides can be obtained from various sources, including bacteria.

[0023] Polyketide biosynthesis is highly complex because the process involves multifunctional enzymes called polyketide synthases (“PKS”). The genes responsible for polyketide biosynthesis are aggregated in the genome, forming BGCs. Each BGC encodes the PKS responsible for the formation of the carbon backbone, along with the adaptation enzymes required for the primary adaptation events, the subsequent adaptation events to form the structure final polyketide, as well as genes encoding for BGC regulation and resistance to the final product where applicable.

[0024] Bacterial aromatic polyketides are generally synthesized by type II PKSs (“TILPKSs”), which are not as well understood as type I or type III PKSs. However, skin-derived TILPKs are not known to have effects for topical skin applications.

[0025] A new TILPKS BGC, TILPKS BGC5 ([Fig. 1]), has now been discovered. Products of this organism are thought to have properties that enhance the skin's barrier function and / or immune defenses. These properties may be beneficial for the treatment of certain skin conditions such as atopic dermatitis. One such product, a new small molecule ("Compound Range 1"), which was purified from an active fraction of skin-derived S. saccharolyticus bacterial extracts, has the following structure:

[0026] Thus, in various embodiments, the disclosure relates to TIL PKS BGC5 products, including molecules from Compound Range 1, and extracts and / or compositions comprising the products.

[0027] It has been surprisingly discovered that TILPKS BGC5 is not present on the skin of people with atopic dermatitis, but is present in healthy individuals. Thus, it is thought that TILPKS BGC5 products, including molecules from Compound Range 1, may have beneficial effects in the treatment of atopic dermatitis.

[0028] It was also surprisingly discovered that, under basal and stimulated conditions mimicking atopic dermatitis in vitro, these purified S. saccharolyticcus extracts induce, in keratinocytes, an upregulation of genes associated with skin barrier function (filaggrin, involucrin, and loricrin), cell differentiation (claudin 1, corneodesmosin, keratin 16, and type I keratin 6A), the production of antimicrobial peptides, and the innate immune response (S100A7, RNASE7, DEFB4A, and PI3). These findings suggest that skin barrier function and / or immune defenses can be enhanced by treatment with S. saccharolyticcus and S. wamei extracts, TIL PKS BGC5 products, and / or Compound Range 1 molecules in vivo.

[0029] Thus, in various embodiments, the disclosure further relates to bacterial extracts containing TII-PKS BGC5 and / or products thereof, including molecules from Compound Range 1, compositions comprising TII-PKS BGC5 and / or products thereof, in particular obtained from S. saccharolyticcus or S. warnei, for example from skin-derived S. saccharolyticcus, and compositions comprising the extracts.

[0030] The compositions may, in various embodiments, be topical compositions. The form of the compositions may vary. For example, the composition may be a cream, lotion, gel, hydrogel, ointment, paste, serum, foam, spray, film, or any form suitable for topical administration to the skin of TILPKS BGC5 and / or any of its products, including molecules from Compound Range 1, or of an extract described herein.Compositions may include one or more additional components suitable for topical administration to the skin of TILPKS BGC5 and / or any of its products, including molecules from Compound Range 1 or an extract described herein, or suitable for skin treatment, for example one or more cosmetically or pharmaceutically acceptable carriers or vehicles (e.g., water and / or non-aqueous solvents such as glycols), penetration or absorption activators, solubility activators, pH correctors, emollients, antioxidants, vitamins, preservatives, etc.

[0031] According to various embodiments, the compositions may comprise TILPKS BGC5 and / or one of its products in an amount ranging from approximately 0.0001%, for example approximately 0.0005%, approximately 0.001%, or approximately 0.005%, up to approximately 25%, for example approximately 18%, up to approximately 15%, up to approximately 12%, up to approximately 10%, up to approximately 8%, up to approximately 5%, up to approximately 4%, up to approximately 3%, up to approximately 2.5%, up to approximately 2%, up to approximately 1.9%, up to approximately 1.8%, up to approximately 1.7%, up to approximately 1.6%, up to approximately 1.5%, up to approximately 1.4%, up to approximately 1.3%, up to approximately 1.2%, up to approximately 1.1% up to approximately 1%, up to approximately 0.9%, up to approximately 0.8%, up to approximately 0.7%, up to approximately 0.6%, up to approximately 0.5%, up to approximately 0.4%, up to approximately 0.3%, up to approximately 0.2%, up to approximately 0.1%, up to approximately 0.09%, up to approximately 0.08%, up to approximately 0.07%up to approximately 0.06%, up to approximately 0.05%, up to approximately 0.04%, up to approximately 0.03%, up to approximately 0.02%, or up to approximately 0.01% by weight, based on the total weight of the composition, including all ranges and subranges using any of the disclosed limits as upper and lower limits.

[0032] According to various embodiments, the extracts may comprise TILPKS BGC5 and / or one of its products in an amount ranging from approximately 1%, for example approximately 5%, approximately 10%, approximately 15%, approximately 20%, or approximately 25%, up to approximately 99.99%, for example, up to approximately 99.95%, up to approximately 99.9%, up to approximately 99.5%, up to approximately 99%, up to approximately 98%, up to approximately 97%, up to approximately 96%, up to approximately 95%, up to approximately 94%, up to approximately 93%, up to approximately 92%, up to approximately 91%, up to approximately 90%, up to approximately 85%, up to approximately 80%, up to approximately 75%, up to approximately 70%, up to approximately 65%, up to approximately 60%, up to approximately 55%, up to approximately 50%, up to approximately 45%, up to approximately 40%, up to approximately 35%, or up to about 30%, based on the total weight of the extract, including all ranges and sub-ranges using any of the disclosed limits as upper and lower limits. SKIN TREATMENT PROCESS

[0033] The disclosure also relates to skin treatment processes. As described herein, TILPKS BGC5 and / or products thereof, including the molecules in Compound Range 1, and extracts and / or compositions containing them, particularly those obtained from skin-derived S. saccharolyticcus or S. wamei, are intended to enhance the skin's barrier function and / or immune defenses, and / or may be useful in treating certain skin conditions such as atopic dermatitis. Various skin treatment processes according to the disclosure therefore relate to: (i) processes for enhancing the skin's barrier function, (ii) processes for enhancing the skin's immune defenses, (iii) processes for treating skin diseases, disorders, and / or conditions, and / or (iv) processes for treating atopic dermatitis.

[0034] In some embodiments, the preceding processes include the application of TILPKS BGC5 and / or one of its products, for example a molecule from Compound Range 1, or an extract or composition containing them, in particular those obtained from S. saccharolyticus or S. wamei, to the skin.

[0035] In other embodiments, the aforementioned processes include the application of TILPKS BGC5 and / or one of its products, for example a molecule from Compound Range 1, or an extract or composition containing them, in particular those obtained from S. saccharolyticcus or S. wamei, derived from the skin, to the skin of a person in need of one or more of the following actions: (i) strengthening the skin barrier function, (ii) strengthening the skin's immune defenses, (iii) treating a skin disease, disorder and / or condition, and / or (iv) treating atopic dermatitis.

[0036] As described herein, the treatment of skin diseases, disorders and / or conditions, such as atopic dermatitis, is intended to refer to the treatment of the disease, disorder and / or condition, such as atopic dermatitis itself, and / or the treatment of one or more symptoms or associated physical effects of the disease, disorder, and / or condition. For example, the symptoms or associated physical effects of atopic dermatitis may include itching, dryness, inflammation, etc. As such, a treatment approach for atopic dermatitis may include treating the skin in a way that alters the skin microbiome to reduce or minimize the incidence of atopic dermatitis, or may include treating the skin in a way that reduces, minimizes, and / or eliminates one or more of these symptoms, for example, itching, dryness, inflammation, etc.

[0037] The methods may include the application of TILPKS BGC5 and / or one of its products, for example a molecule from Compound Range 1, or an extract or composition containing them, once or more times a day, for example twice a day or more, three times a day or more, etc., as needed or desired. There is no limit to the duration of this application.The application may take place once or several times a day, for example at least twice a day or at least three times a day, for a period of at least 2 days, for example at least 3 days, at least 5 days, at least 7 days, at least 10 days, at least 12 days, at least two weeks, at least three weeks, at least four weeks, at least five weeks, at least 6 weeks, at least two months, at least three months, at least four months, at least five months, at least six months, at least nine months, at least 12 months, at least 18 months, at least two years, etc., as required to provide the desired effect, for example, for strengthening the skin barrier, strengthening the skin's immune defenses, treating atopic dermatitis, etc.

[0038] It will be evident that modifications and variations of the embodiments herein are possible without departing from the scope of the disclosure. Furthermore, it should be noted that all the examples in this disclosure, while illustrating various embodiments of the disclosure, are provided as non-limiting examples and should therefore not be considered as limiting the different aspects thus illustrated. It should be understood that all definitions herein are provided only for this disclosure.

[0039] As used herein, the terms “treat”, “treatment” or similar, with respect to diseases, disorders and conditions of the skin, are intended to include any degree of treatment.

[0040] As used herein, the terms “strengthening”, “reinforcing” or similar, with respect to the skin barrier function, are intended to denote any improvement or increase in the epidermal differentiation of the treated skin, the barrier function against pathogens and / or the hydration barrier function.

[0041] As used herein, the terms “enhance”, “strengthening” or similar, with respect to the skin’s immune system, are intended to denote any improvement or increase in the ability of the treated skin to maintain a healthy microbiome balance and / or to reduce, inhibit or eliminate pathogenic microbes.

[0042] As used herein, the term "extract" is intended to refer to a formulation or mixture of compounds isolated from S. saccharolyticcus or S. wamei.

[0043] As used herein, the terms "purified extract" are intended to refer to a concentrated formulation or mixture of compounds isolated from S. saccharolyticcus or S. warnei.

[0044] The expression "and / or" should be understood as including both conjunctive and disjunctive clauses. For example, "treat and / or prevent" means "treat and prevent" as well as "treat or prevent," and expressly covers cases of either.

[0045] For the purposes of this disclosure, it should be noted that, for the sake of brevity, some of the quantitative expressions given herein are not qualified with the term "approximately". It is understood that the term "approximately", whether used explicitly or implicitly, means that each quantity given herein is intended to refer to the actual value given, and is also intended to refer to the approximation of that given value that would be reasonably deduced based on the ordinary skills of the art, including approximations due to the experimental and / or measurement conditions for that given value, unless otherwise stated.

[0046] All ranges and quantities stated herein are intended to include subranges and quantities using any disclosed point as a boundary, and all boundaries are intended to be included unless expressly stated otherwise. Thus, a range of "1% to 10%, such as 2% to 8%, such as 3% to 5%", is intended to encompass ranges of "1% to 8%", "1% to 5%", "2% to 10%", and so on. All numbers, quantities, ranges, etc., are intended to be modified by the term "approximately", whether or not expressly stated, unless expressly stated otherwise. Similarly, a given range of "approximately 1% to 10%" is intended to have its boundaries of both 1% and 10% modified by the term "approximately". The term "approximately" is used here to indicate a difference of up to + / - 10% from the stated number, such as + / - 9%, + / - 8%, + / - 7%, + / - 6%, + / - 5%, + / - 4%, + / - 3%, + / - 2%, or + / - 1%.Unless expressly stated otherwise, "approximately" means + / - 5%. Similarly, all range boundaries are understood to be disclosed individually, such that, for example, a range of 1:2 to 2:1 is understood to disclose a ratio of 1:2 and 2:1.

[0047] As used herein, all the ranges provided are intended to include each specific range within the given ranges, as well as each combination of sub- intermediate ranges. Thus, a range from 1 to 5 specifically includes 1, 2, 3, 4 and 5, as well as sub-ranges such as 2 to 5, 3 to 5, 2 to 3, 2 to 4, 1 to 4, etc.

[0048] Unless expressly stated otherwise, no process described herein is intended to be interpreted as requiring that its steps be performed in a specific order. Consequently, where a process claim does not expressly specify an order for its steps to be followed, or where it is not specifically stated in the claims or descriptions that the steps must be limited to a specific order, no particular order is to be inferred.

[0049] The following examples are intended to illustrate embodiments of this disclosure but are not exhaustive. It will be obvious to those skilled in the art that various modifications and variations can be made to the compositions and processes of the invention without departing from the spirit or scope of the invention. Therefore, this disclosure is intended to cover modifications and variations that fall within the scope of the appended claims and their equivalents. EXAMPLES

[0050] The following examples are only intended to be non-limiting and explanatory in nature. Example 1

[0051] Identification of a new organism producing TII-PK BCG

[0052] Using a known algorithm (MetaBGC, (9§§)) and metagenomic sequencing data (2§), skin samples taken from individuals with atopic dermatitis (AD-positive) and without atopic dermatitis (AD-negative) were studied. The results of these studies are shown in Table 1:

[0053] [Table 1] TABLE 1 TII-PKS Plasmid-positive TII-PKS Plasmid-negative- TOTAL DA-positive (n = 350) 0 350 350 DA-negative (n = 1126) 36 1090 1126 Total (n = 1476) 36 1440 1476 Risk* o** 0.243** 0.237

[0054] *Risk report, 0

[0055] **p = 4e5 by one-sided Fisher's exact test

[0056] This in silico analysis shows that TILPKS-BGC5 is present only in individuals with healthy skin (DA-negative). The genetic organization of TILPKS- BGC5 is shown in [Fig.1] (indicating the annotation of each gene as well as the NCBI close query). Example 2

[0057] Identification of the molecule from the range of compounds 1

[0058] Approximately 100 cells of a strain of S. saccharolyticcus with confirmed presence of TIL PKS-BGC5 were cultured in tryptic soybean broth (TSB) under anaerobic conditions at 37 °C. After five days, the cell pellets were extracted by repeated sonication in ethyl acetate, and the extract was then dried under vacuum. The dried crude extract was subsequently fractionated on several chromatographic columns to obtain fractions of varying polarity, and the fractions were evaluated by UV absorbance ([Fig. 2]).

[0059] A new molecule from Compound Range 1 was discovered in one of the fractions, identified by UV absorbance ([Fig.3A]), HMBC (Heteronuclear Multiple Bond Correlation) NMR spectroscopy ([Fig.3B]) and mass spectrometry ([Fig.3C]). Example 3

[0060] Biological activity of the molecule from the range of compounds 1

[0061] In order to evaluate the biological activity of the molecule in the range of compounds 1. Identified in Example 2, in vitro models of primary 2D human epidermal keratinocytes from a healthy donor (“normal model”) and the same keratinocytes stimulated with S. aureus (“DA-type model”) were used. Basal and infected NHEKs were treated with an extract of S. saccharolyticcus (n = 3). RNA was extracted from cell cultures treated with S. saccharolyticcus extract and untreated (control) cultures 48 hours after incubation, and qPCR analysis was performed to analyze gene expression. The results of these studies are shown in FIGS. 4A–4B and 5A–5B (the y-axis represents relative gene expression).

[0062] Figures 4A-4B show that purified S. saccharolyticcus extracts induce upregulation of genes associated with skin barrier function (FLG, IVL, and LOR) and genes associated with cell differentiation (CLDN1, TGM1, KRT16, and KRT6A) in normal and / or DA-type models. Figures 5A-5B show that purified S. saccharolyticcus extracts increase the expression of antimicrobial peptides and innate immune genes involved in immune defenses (S100A7, RNASE7, DEFB4A, and PI3) in normal and / or DA-type models.

[0063] The above results demonstrate that a skin-derived extract of S. saccharolyticcus bacteria surprisingly strengthens the skin's barrier function and the immune defenses in in vitro models of atopic dermatitis. Based on these results, it is estimated that the molecules of Compound Range 1, an extract of S. saccharolyticcus bacteria, particularly derived from skin, from strains encoding Compound Range 1 and compositions including Compound Range 1 molecules and / or the extract can be used in vivo to strengthen the skin's barrier function and immune defenses, and to treat skin diseases, disorders and conditions such as atopic dermatitis.

[0064] The following elements are cited here: • (1) Ahle CM, Stpdkilde K, Afshar M, Poehlein A, Ogilvie LA, Sôderquist B, Hüpeden J, Brüggemann H. Staphylococcus saccharolyticus: An Overlooked Human Skin Colonizer. Microorganisms. 2020 Jul 23;8(8): 1105 (doi: 10.3390 / microorganisms8081105); • (2§) Byrd AL, Belkaid Y, Segre JA. The human skin microbiome. Nat Rev Microbiol. 2018 Mar;16(3):143-155 (doi: 10.1038 / nrmicro.2017.157); • (3) Nakatsuji T, Chen TH, Narala S, Chun KA, Two AM, Yun T, Shafiq F, Kotol PF, Bouslimani A, Melnik AV, Latif H, Kim JN, Lockhart A, Artis K, David G, Taylor P, Streib J, Dorrestein PC, Grier A, Gill SR, Zengler K, Hata TR, Leung DY, Gallo RL. Antimicrobiais from human skin commensal bacteria protect against Staphylococcus aureus and are déficient in atopie dermatitis. Sci Transi Med. 2017 Feb 22;9(378):eaah4680 (doi: 10.1126 / scitranslmed.aah4680); • (4) Nakatsuji T, Cheng JY, Gallo RL. Mechanisms for control of skin immune function by the microbiome. Curr Opin Immunol. 2021 Oct;72:324-330 (doi: 10.1016 / j.coi.2021.09.001); • (5) Nakatsuji T, Gallo RL. Ann Allergy Asthma Immunol. The rôle of the skin microbiome in atopie dermatitis. 2019 Mar;122(3):263-269 (doi: 10.1016 / j.anai.2018.12.003); • (6) Nodake Y, Matsumoto S, Miura R, Honda H, Ishibashi G, Matsumoto S, Dekio I, Sakakibara R. Pilot study on novel skin care method by augmentation with Staphylococcus epidermidis, an autologous skin microbe—A blinded randomized clinical trial. J Dermatol Sci. 2015 Aug;79(2): 119-26 (doi: 10.1016 / j.jdermsci.2015.05.001); • (7) O'Neill AM, Nakatsuji T, Hayachi A, Williams MR, Mills RH, Gonzalez DJ, Gallo RL. Identification of a Human Skin Commensal Bacterium that Selectively Kills Cutibacterium acnés. J Invest Dermatol. 2020 Aug;140(8):1619-1628.e2 (doi: 10.1016 / j.jid.2019.12.026); (8) Simonart T, Dramaix M, De Maertelaer V. Efficacy of tetracyclines in the treatment of acné vulgaris: a review. Br J Dermatol. 2008 Feb; 158(2):208-1 (doi: 10.1111 / j. 1365-2133.2007.08286); (9§§) Sugimoto Y, Camacho FR, Wang S, Chankhamjon P, Odabas A, Biswas A, Jeffrey PD, Donia MS. A metagenomic strategy for harnessing the chemical repertoire of the human microbiome. Science. 2019 Dec 13;366(6471):eax9176; (10) Zheng Y, Hunt RL, Villaruz AE, Fisher EL, Lin R, Lin Q, Cheung GYC, Li M, Otto M. Commensal Staphylococcus epidermidis contributes to skin barrier homeostasis by generating protective ceramides. Cell Host Microbe. 2022 Mar 9;30(3):301–313.e9; (11) Zhu X, Siitonen V, Melanchon CE, Metsa-Ketel M. ACS Synth Biol. Biosynthesis of Diverse Type II Polyketide Core Structures in Streptomyces coelicolor M1152. 2021 Feb 19; 10(2):243–251(doi:10.1021 / acssynbio.0c00482).

Claims

1. Demands Extract of S. saccharolyticcus or S. wamei bacteria derived from skin comprising a compound with the following formula:

2. Extract of S. saccharolyticcus or S. wamei bacteria according to claim 1, comprising a total amount of said compound(s) in an amount of about 1% to about 99.99%, preferably about 99.95%, more preferably about 99.9%, more preferably about 99.5%, most preferably about 99% by weight, based on the total weight of the extract.

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