NOVEL SMALL MOLECULES AND METHODS USING THEM FOR SKIN TREATMENT

Abstract

NOVEL SMALL MOLECULES AND METHODS OF USE THEREOF FOR SKIN TREATMENT The disclosure relates to novel biosynthetic gene clusters that encode type II polyketides, products thereof, extracts and compositions comprising the products, and methods of using the products, extracts and compositions for skin treatment, for example, for enhancing the barrier function and / or immune defenses of the skin. Figure for abstract: none

Description

Title of the invention: NOVEL SMALL MOLECULES AND METHODS USING THEM FOR SKIN TREATMENT Technical field

[0001] The present disclosure relates to small molecules, extracts and compositions comprising the molecules, and methods using them for the treatment of the skin, for example to enhance the barrier function and / or immune defenses of the skin. 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. In circumstances where the barrier is broken, or when the balance between commensal bacteria and pathogens is disturbed, skin diseases or disorders may occur.

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

[0004] Coagulase-negative staphylococci (CNS) are a heterogeneous group of bacteria that are less frequently associated with infections in humans than species that possess a broad range of virulence factors, such as S. aureus. For example, one strain of CNS, Staphylococcus saccharolyticcus, is part of the skin microbiota that rarely causes infections in humans. S. saccharolyticus requires delicate growth conditions compared to other CNS strains and has only recently been precisely identified. However, S. saccharolyticus has received little research to date. Another example of SCN in the skin microbiota is Staphylococcus warnei. Although they are considered predominant skin colonizers, the role of S. saccharolyticcus and S. wamei in skin homeostasis and skin health has been relatively poorly characterized.

[0005] There is therefore still a need 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 practice routine or preventative skin care in an effort to improve the appearance or health of the skin in general, and / or to treat specific skin problems. For example, consumers seek cosmetic skin care products that temporarily or permanently delay or eliminate the signs of aging, counteract negative environmental influences, prevent dehydration, etc.

[0007] Furthermore, the formulation of environmentally friendly cosmetic products, which are designed and developed with environmental issues in mind, is becoming a major objective in a bid to address global challenges. It is, therefore, essential to provide more sustainable compositions, preparation processes and ingredients to address these environmental concerns. In this context, it is important to develop new cosmetic products and processes with a better carbon footprint, in particular by promoting the use of renewable raw materials and / or cosmetic compositions with a good naturalness index and / or materials of natural origin and, more particularly, by reducing the use of compounds of petrochemical origin.

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

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

[0010] The disclosure also relates to a range of novel polycyclic aromatic polyketides (“Range of Compounds 1”), extracts and compositions comprising the molecules, and methods for treating skin with the molecules, for example to improve or strengthen the skin's barrier function, improve 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, e.g., bacterial extracts derived from skin, compositions comprising the bacterial extracts, and methods for treating skin with the bacterial extracts and / or compositions, e.g., for improving or strengthening the barrier function of the skin, strengthening the immune defenses of the skin, and / or treating 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 the bacterial extracts, and methods for treating skin with the bacterial extracts and / or compositions, for example, for improving or strengthening the barrier function of the skin, improving the immune defenses of the skin, and / or treating various types of skin diseases or conditions.

[0013] In some embodiments, the methods of treating the skin are methods for enhancing the barrier function of the skin. In other embodiments, the methods of treating the skin are methods for enhancing the immune defenses of the skin. In still other embodiments, the methods of treating the skin are methods for treating a skin disease, condition, or disorder. For example, the methods may be methods for treating atopic dermatitis.

[0014] The products of the novel biosynthetic gene clusters that encode type II polyketides, including Compound Series 1 molecules, S. saccharolyticcus bacterial extracts, and S. warnei bacterial extracts can also be used as a biomarker. 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.l] [Fig.l] shows the genetic organization of TILPKS BGC5 in S. saccharolyticcus and S. warnei.

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

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

[0018] [Fig 4A-4B] [Fig.4A]-4B show graded results of upregulation of genes associated with skin barrier function (FLG, IVL and LOR), and 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] [Fig.5A]-5B show graded results of increased 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 that encode type II polyketides, products thereof including 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 methods of treating skin. The products and / or molecules can also be used as biomarkers for detecting 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, e.g., bacterial extracts derived from skin. The extracts are preferably purified. In other embodiments, the disclosure relates to products in the extracts, e.g., 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, e.g., antibacterial, antifungal, anticancer, antiviral, immunosuppressive, anticholesterolemic, and anti-inflammatory activity. Polyketides can be obtained from a variety of sources, including bacteria.

[0023] Polyketide biosynthesis is very complex because the process involves multifunctional enzymes called polyketide synthases (“PKSs”). 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 skeleton, together with the adaptation enzymes required for the primary adaptation events, subsequent adaptation events to form the structure final polyketide, as well as genes coding 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 novel TILPKS BGC, TILPKS BGC5 ([Fig.l]) has now been discovered. Products of this organism are believed to have properties that enhance the barrier function and / or immune defenses of the skin. These properties may be beneficial for the treatment of certain skin conditions such as atopic dermatitis. One such product, a novel small molecule (“Compound Range 1”), which has been purified from an active fraction of skin-derived S. saccharolyticcus bacterium extracts, has the following structure:

[0026] Thus, in various embodiments, the disclosure relates to TIL PKS BGC5 products, including Compound Family 1 molecules, 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 people. Thus, it is believed that TILPKS BGC5 products, including the molecules of Compound Range 1, may have beneficial effects for 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), 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 of 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 a product thereof, including molecules of Compound Range 1, or an extract described herein.The compositions may comprise one or more additional components suitable for topical administration to the skin of TILPKS BGC5 and / or a product thereof, including molecules of Compound Range 1 or an extract described herein, or suitable for treatment of the skin, 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 enhancers, solubility enhancers, pH adjusters, emollients, antioxidants, vitamins, preservatives, etc.

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

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

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

[0034] In some embodiments, the foregoing methods comprise applying TILPKS BGC5 and / or a product thereof, for example a molecule of 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 methods comprise applying TILPKS BGC5 and / or a product thereof, for example a molecule of 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 barrier function of the skin, (ii) strengthening the immune defenses of the skin, (iii) treating a skin disease, disorder and / or condition, and / or (iv) treating atopic dermatitis.

[0036] As described herein, 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 associated symptoms or physical effects of the disease, disorder and / or condition. For example, the associated symptoms or physical effects of atopic dermatitis may include pruritus, dryness, inflammation, etc. As such, a method of treating atopic dermatitis may include treating the skin so as to alter the skin microbiome to reduce or minimize the incidence of atopic dermatitis, or may include treating the skin so as to reduce, minimize and / or eliminate one or more of these symptoms, e.g. pruritus, dryness, inflammation, etc.

[0037] The methods may comprise applying TILPKS BGC5 and / or a product thereof, for example a molecule of Compound Range 1, or an extract or composition containing them, one or more times a day, for example twice a day or more, three or more times a day, etc., as needed or desired. The period during which this application may continue is not limited.The application may take place one or more 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 apparent that modifications and variations of the embodiments herein are possible without departing from the scope of the disclosure. Further, it should be noted that all examples of the present disclosure, while illustrating various embodiments of the disclosure, are provided as non-limiting examples and therefore should not be construed as limiting the various aspects thus illustrated. It should be understood that all definitions herein are provided for the present disclosure only.

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

[0040] As used herein, the terms "enhance", "strengthen" or the like, with respect to skin barrier function, are intended to mean any improvement or increase in the treated skin's epidermal differentiation, pathogen barrier function and / or moisture barrier function.

[0041] As used herein, the terms "enhance," "strengthen," or the like, with respect to the skin's immune system, are intended to mean any improvement or increase in the ability of the treated skin to maintain a healthy microbiome balance and / or 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 to include both the conjunctive and the disjunctive. 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, to provide a more concise description, some of the quantitative expressions given herein are not qualified with the term "about." It is understood, that the term "about," whether used explicitly or not, that each quantity given herein is intended to refer to the actual value given, and that it is also intended to refer to the approximation to that given value that would be reasonably deduced based on ordinary skill in the art, including approximations due to experimental and / or measurement conditions for that given value, unless otherwise indicated.

[0046] All ranges and quantities set forth herein are intended to include subranges and quantities using any disclosed point as a bound, and all bounds are intended to be inclusive 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 “about,” whether or not expressly stated, unless expressly stated otherwise. Similarly, a given range of “about 1% to 10%” is intended to have both its 1% and 10% bounds modified by the term “about.” The term "approximately" is used herein 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 otherwise expressly stated, “approximately” means + / - 5%. Similarly, all range boundaries are understood to be individually disclosed, 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 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 of 1 to 5 specifically includes 1, 2, 3, 4, and 5, as well as subranges such as 2 to 5, 3 to 5, 2 to 3, 2 to 4, 1 to 4, etc.

[0048] Unless otherwise expressly stated, it is in no way intended that any method disclosed herein be construed as requiring that its steps be performed in any specific order. Accordingly, where a method claim does not expressly recited an order to be followed by its steps or it is not specifically stated in the claims or descriptions that the steps are to be limited to a specific order, it is not intended to infer any particular order therefrom.

[0049] The following examples serve to illustrate embodiments of the present disclosure without being limiting in nature. It will be apparent to those skilled in the art that various modifications and variations may be made in the compositions and methods of the invention without departing from the spirit and scope of the invention. Thus, it is intended that the present disclosure cover modifications and variations that fall within the scope of the appended claims and their equivalents. EXAMPLES

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

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

[0052] Using a known algorithm (MetaBGC, (9§§)) and metagenomic sequencing data (2§), samples taken from the skin of people 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 ratio, 0

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

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

[0057] Identification of the molecule of the Compound Range 1

[0058] Approximately 100 1 of a S. saccharolyticcus strain with confirmed presence of PKS-BGC5 TILs were cultured in tryptic soy broth (TSB) under anaerobic conditions at 37 °C. After five days, the cell pellets were extracted by repeated sonication in ethyl acetate, and then the extract was dried under vacuum. The dried crude extract was then fractionated on several chromatography columns to obtain fractions of varying polarity, and the fractions were evaluated by UV absorbance ([Fig. 2]).

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

[0060] Biological activity of the molecule of the Range of compounds 1

[0061] In order to evaluate the biological activity of the molecule of the Range of compounds 1 identified in Example 2, in vitro models of 2D primary human epidermal keratinocytes from a healthy donor (“normal model”) and the same keratinocytes stimulated with S. aureus (“DA-like model”) were used. Basal and infected NHEKs were treated with S. saccharolyticcus extract (n = 3). RNA was extracted from S. saccharolyticcus extract-treated and untreated (control) cell 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 (y-axis represents relative gene expression).

[0062] [Fig.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 AD-like models. [Fig.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 AD-like models.

[0063] The above results demonstrate that an extract of S. saccharolyticcus bacteria derived from the skin surprisingly strengthens the barrier function of the skin and the immune defenses in in vitro models of atopic dermatitis. Based on these results, it is believed that the molecules of Compound Range 1, an extract of S. saccharolyticcus bacteria, in particular derived from the skin, from strains encoding Compound Range 1 and compositions comprising molecules of Compound Range 1 and / or the extract can be used in vivo to strengthen the barrier function and immune defenses of the skin, 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. Claims Extract of S. saccharolyticcus or S. wamei bacteria derived from skin comprising a compound of formula:

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

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