Leveraging bacteria in the skin microbiome


Azitra’s core technology uses three key strategies that leverage desirable bacteria naturally found in the skin microbiome such as Staphylococcus epidermidis (SE):

Skin Commensal Bacteria and SE

To create novel products to treat skin disease and improve skin appearance, Azitra is harnessing the beneficial properties of SE. Skin commensal bacteria offer many well-described and documented benefits that can potentially be harnessed to improve skin appearance for therapeutic applications. These commensal bacteria, including many strains of Staphylococcus epidermidis (SE), have adapted to live with us and cross-talk with the human immune system to create homeostasis. In certain skin diseases or cases of dysbiosis, direct application of commensal bacteria like SE can treat dysbiosis or microbes associated with disease—as well as skin inflammation, tissue damage, or a weakened skin barrier.

Additionally, SE is an excellent colonizer of human skin, naturally abundant and able to grow on all human skin types. Upon skin colonization, SE can:

Product goals:

  • Treat dysbiosis and microbes associated with disease
  • Improve skin barrier function
  • Accelerate wound healing and tissue repair
  • Address cutaneous inflammation

SE Engineered for Therapeutic Targets

The microbiome and specific strains that live with us can also be designed to deliver effective therapy to the skin by using the tools of genetic engineering. Azitra engineers commensal skin bacteria to deliver critical missing natural proteins and disease-modifying proteins directly to the target and through the stratum corneum of the skin. This approach constitutes a major platform technology which can target multiple diseases by delivering different proteins to the target in the skin.

These types of products are known as Live Biotherapeutic Products (LBPs) and are being developed as cost-effective topical applications with the potential to solve skin disease challenges. The advantages of such LBPs include the ability to directly address the cause of disease, ease of use, and topical application at the location of the skin problem—thus avoiding systemic therapy. Azitra is focused on LBPs that treat disease and control health care costs. Many diseases, including ichthyosis vulgaris and multiple orphan diseases such as Netherton syndrome, are the result of deficient or missing proteins in the skin. The microbiome (and specifically Staphylococcus epidermidis) can be engineered to deliver the missing proteins that can help resolve the underlying disease, and using the natural commensal bacteria to do this also addresses the challenges of dysbiosis that is frequently a major contributing factor to the disease symptoms and severity.

The benefits of this approach include slow, stable, consistent and effective release of protein, at the level of the target cell in the skin. Azitra has pioneered this work and established many of the foundation patents in the space. Azitra’s work is rapidly progressing to clinical testing and product introduction.

Key products:

  • Filaggrin to restore the skin barrier
  • LEKTI to restore missing protease inhibitor and treat Netherton syndrome
  • IL-10 to suppress inflammation

SE as a Source of Bioactive Drug Products

Azitra has established a discovery-stage platform focused on the identification and development of bioactive compounds that can be derived from commensal bacterial strains. These compounds can be used directly as standalone products or paired with commensal bacteria for treating disease and addressing skin appearance.

Funded by Azitra and through multiple grants, Azitra is working with the skin microbiome team at the Jackson Laboratory in Farmington, CT to explore the products produced by S. epidermidis (SE) that can offer potential to treat skin disease. It has been well established that SE produces multiple unique biological products with potentially important therapeutic benefits. Azitra is pleased to be a critical element of the team exploring the promise of such products.

Target programs:

  • New antibiotic candidates targeting S. aureus
  • Compounds to inhibit biofilm of invasive organisms
  • Novel therapeutic candidates for ichthyosis, atopic dermatitis and other skin diseases
  • Development of advanced biosensors that respond to invasive or dysbiotic organisms

Publications

Research from Azitra affiliates

Dodds D., Whitfill T., et al ., Controlling the Growth of the Skin Commensal Staphylococcus epidermidis Using d-Alanine Auxotrophy MSphere, Jun 2020, 5 (3) e00360-20

Kong, H.H., Oh, J., et al., Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis. Genome Res, 2012. 22(5): p. 850-9.

Oh, J., et al., Biogeography and individuality shape function in the human skin metagenome. Nature, 2014. 514(7520): p. 59-64

Oh, J., et al., The altered landscape of the human skin microbiome in patients with primary immunodeficiencies. Genome Res, 2013. 23(12): p. 2103-14.

Oh, J., et al., Temporal Stability of the Human Skin Microbiome. 5;165(4):854-66.

Oh, J., et al., Shifts in human skin and nares microbiota of healthy children and adults. Genome Med, 2012. 10;4(10):77.


Independent

S. epidermidis-specific

Stacy A., Belkaid Y. Microbial guardians of skn Health. Science. 2019. 18;363(6424):227-228

Linehan, J.L., et al., Non-classical Immunity Controls Microbiota Impact on Skin Immunity and Tissue Repair. Cell, 2018.

Nakatsuji, T., et al., Antimicrobials from human skin commensal bacteria protect against Staphylococcus aureus and are deficient in atopic dermatitis. Sci Transl Med, 2017. 9(378).

Scharschmidt, T.C., et al., Commensal Microbes and Hair Follicle Morphogenesis Coordinately Drive Treg Migration into Neonatal Skin. Cell Host Microbe, 2017. 21(4): p. 467-477.e5.

Naik, S., et al., Commensal-dendritic-cell interaction specifies a unique protective skin immune signature. Nature, 2015. 520(7545): p. 104-8.

Scharschmidt, Tiffany C., et al., A Wave of Regulatory T Cells into Neonatal Skin Mediates Tolerance to Commensal Microbes. Immunity, 2015. 43(5): p. 1011-1021

Nodake, Y., et al., 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. 79(2): p. 119-26.

Skin microbiome reviews

Belkaid, Y. and O.J. Harrison, Homeostatic Immunity and the Microbiota. Immunity, 2017. 46(4): p. 562-576.

Byrd, A.L., et al., Staphylococcus aureus and Staphylococcus epidermidis strain diversity underlying pediatric atopic dermatitis. Science translational medicine, 2017. 9(397): p. eaal4651.

Belkaid, Y. and S. Tamoutounour, The influence of skin microorganisms on cutaneous immunity. Nat Rev Immunol, 2016. 16(6): p. 353-66.

Grice, E.A. and J.A. Segre, The skin microbiome. Nat Rev Microbiol, 2011. 9(4): p. 244-53

Naik, S., et al., Compartmentalized control of skin immunity by resident commensals. Science, 2012. 337(6098): p. 1115-9.

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