Accelerated skin wound healing by selective 11β-Hydroxylase (CYP11B1) inhibitors

Emmerich, Juliette; Koppen, Chris J. van; Burkhart, Jens L.; Engeli, Roger T.; Hu, Qingzhong; Odermatt, Alex; Hartmann, Rolf W.

doi:10.1016/j.ejmech.2017.11.018

Cited by 10 publications

(7 citation statements)

References 36 publications

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“…Furthermore, our animal model provides the basis and flexibility to be used for combination therapy, e.g. by (i) combining our compounds with standard-of-care antibiotics or compounds, whose activity is not directed against bacteria but for example against cortisol biosynthesis in skin (45). Also, (ii) the use of pathogens other than S. aureus to infect wounds may be considered, e.g.…”

Section: Discussionmentioning

confidence: 99%

“…The rapid provision of valuable preclinical data is extremely useful for the design and synthesis of such new compounds. Furthermore, our animal model provides the basis and flexibility to be used for combination therapy, e.g ., by (i) combining our compounds with standard-of-care antibiotics or compounds whose activity is not directed against bacteria but, for example, against cortisol biosynthesis in skin . Also, (ii) the use of pathogens other than S. aureus to infect wounds may be considered, e.g ., perilous wound-infecting bacteria such as Streptococcus pyogenes , Pseudomonas aeruginosa , and Clostridium perfringens . , …”

Section: Discussionmentioning

confidence: 99%

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Evaluation of Bacterial RNA Polymerase Inhibitors in a Staphylococcus aureus-Based Wound Infection Model in SKH1 Mice

et al. 2020

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Chronic wounds infected with pathogens such as Staphylococcus aureus represent a worldwide health concern, especially in patients with a compromised immune system. As antimicrobial resistance has become an immense global problem, novel antibiotics are urgently needed. One strategy to overcome this threatening situation is the search for drugs targeting novel binding sites on essential and validated enzymes such as the bacterial RNA polymerase (RNAP). In this work, we describe the establishment of an in vivo wound-infection model based on the pathogen S. aureus and hairless Crl:SKH1-Hrhr (SKH1) mice. The model proved to be highly useful to study selected RNAP inhibitors after topical application. Encouraging results were obtained for Rifampicin and the ureidothiophene-2-carboxylic acid 1, for which we hereby also present the cocrystal structure with RNAP. Both compounds showed promising effects on the S. aureus-induced body weight loss, on the kinetics of wound healing and on the number of colony forming units in the wound. This in vivo infection model enables useful insights into the in vivo performance of novel anti-infectives, thus serving as a valuable preclinical tool.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Evaluation of Bacterial RNA Polymerase Inhibitors in a Staphylococcus aureus-Based Wound Infection Model in SKH1 Mice

et al. 2020

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“…Estrogens control female development and fertility but can promote breast cancer proliferation, and selective inhibitors of CYP19A1 treat estrogen-responsive breast cancer (10). Selective inhibitors of CYP11B1 or CYP11B2 are of similar clinical interest (11)(12)(13)(14)(15)(16)(17) for Cushing's disease and hypertension. The development of such inhibitors has been impeded by the 93% amino acid sequence identity between them and their similar steroid-binding functionality.…”

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confidence: 99%

Structure of human cortisol-producing cytochrome P450 11B1 bound to the breast cancer drug fadrozole provides insights for drug design

Brixius‐Anderko

Scott

2019

Journal of Biological Chemistry

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“…This indicates that this enzyme is relevant for tissue remodeling after inflammation [35,79]. Such effects were also observed upon metyrapone treatment, which resulted in accelerated wound healing of human skin ex vivo and in vivo [80]. Moreover, in mice with colitis, metyrapone inhibited TNF-α-induced glucocorticoid synthesis [81].…”

Section: Discussionmentioning

confidence: 88%

Cortisol Metabolism in Carp Macrophages: A Role for Macrophage-Derived Cortisol in M1/M2 Polarization

Maciuszek

Kłak

Rydz

et al. 2020

IJMS

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Macrophages are crucial not only for initiation of inflammation and pathogen eradication (classically polarized M1 macrophages), but also for inflammation inhibition and tissue regeneration (alternatively polarized M2 macrophages). Their polarization toward the M1 population occurs under the influence of interferon-γ + lipopolysaccharide (IFN-γ + LPS), while alternatively polarized M2 macrophages evolve upon, e.g., interlukin 4 (IL-4) or cortisol stimulation. This in vitro study focused on a possible role for macrophage-derived cortisol in M1/M2 polarization in common carp. We studied the expression of molecules involved in cortisol synthesis/conversion from and to cortisone like 11β-hydroxysteroid dehydrogenase type 2 and 3. (11β-HSD2 and 3) and 11β-hydroxylase (CYP11b), as well as the expression of glucocorticoid receptors (GRs) and proliferator-activated receptor gamma (PPARγ) in M1 and M2 macrophages. Lastly, we analyzed how inhibition of these molecules affect macrophage polarization. In M1 cells, upregulation of gene expression of GRs and 11β-HSD3 was found, while, in M2 macrophages, expression of 11β-hsd2 was upregulated. Moreover, blocking of cortisol synthesis/conversion and GRs or PPARγ induced changes in expression of anti-inflammatory interleukin 10 (IL-10). Consequently, our data show that carp monocytes/macrophages can convert cortisol. The results strongly suggest that cortisol, via intracrine interaction with GRs, is important for IL-10-dependent control of the activity of macrophages and for the regulation of M1/M2 polarization to finally determine the outcome of an infection.

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Accelerated skin wound healing by selective 11β-Hydroxylase (CYP11B1) inhibitors

Cited by 10 publications

References 36 publications

Evaluation of Bacterial RNA Polymerase Inhibitors in a Staphylococcus aureus-Based Wound Infection Model in SKH1 Mice

Evaluation of Bacterial RNA Polymerase Inhibitors in a Staphylococcus aureus-Based Wound Infection Model in SKH1 Mice

Structure of human cortisol-producing cytochrome P450 11B1 bound to the breast cancer drug fadrozole provides insights for drug design

Cortisol Metabolism in Carp Macrophages: A Role for Macrophage-Derived Cortisol in M1/M2 Polarization

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