Inhibition and Activity Regulation of Bacterial Collagenases

Schönauer, Esther; Brandstetter, Hans

doi:10.1007/7355_2016_9

Cited by 7 publications

(6 citation statements)

References 148 publications

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“…Doxycycline, a FDA-approved tetracycline antibiotic, has aroused increasing interest as an inhibitor of matrix-metalloproteinases (MMPs) and bacterial collagenases [ 24 – 27 ]. The CCH belongs to the group of calcium-dependent metalloproteases with other cations (e.g.…”

Section: Introductionmentioning

confidence: 99%

“…The CCH belongs to the group of calcium-dependent metalloproteases with other cations (e.g. zinc) mediating the enzyme´s stability, conformation and activity [ 24 ]. Besides their antibacterial properties, tetracyclines can act as chelators for multivalent metal-cations, such as calcium and zinc, and subsequently inhibit excessive collagenase activity [ 24 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

“…zinc) mediating the enzyme´s stability, conformation and activity [ 24 ]. Besides their antibacterial properties, tetracyclines can act as chelators for multivalent metal-cations, such as calcium and zinc, and subsequently inhibit excessive collagenase activity [ 24 , 28 ]. This property and the ability to accumulate in skin tissue make doxycycline a potential skin-protective agent in the setting of CCH-injections.…”

Section: Introductionmentioning

confidence: 99%

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Oral doxycycline prevents skin-associated adverse effects induced by injectable collagenase in a rodent model of capsular contracture around silicone implants

et al. 2022

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Background The collagenase of the bacterium Clostridium histolyticum (CCH) is already an established treatment for fibroproliferative diseases like M. Dupuytren and M. Peyronie Although results are comparable to surgical intervention, skin laceration is a severe and relevant side effect. Doxycycline (DOX) recently rose interest as an inhibitor of matrix-metalloproteinases alongside its capabilities of skin accumulation. It therefore might be a potential skin protective agent in the use of CCH. Methods For simulation of a fibroproliferative disease adjacent to the skin, we utilized a rodent model of capsular fibrosis involving silicone implants and subsequent fibrotic capsule formation. For in-vitro studies, fibrotic capsules were excised and incubated with 0.9 mg/ml CCH and four different doses of DOX. For in-vivo experiments, animals received 0.0, 0.3 or 0.9 mg/ml CCH injections into the fibrotic capsules with or without prior oral DOX administration. Outcome analysis included histology, immunohistochemistry, gene expression analysis, chemical collagen and DOX concentration measurements as well as μCT imaging. Results In-vitro, DOX showed a dose-dependent inhibition of CCH activity associated with increasing capsule thickness and collagen density and content. In-vivo, oral DOX administration did neither interfere with capsule formation nor in effectiveness of CCH dissolving fibrotic capsule tissue. However, skin thickness and especially collagen density was significantly higher compared to control groups. This led to a reduced rate of clinical skin lacerations after DOX administration. Conclusion DOX inhibits CCH and accumulates in the skin. Thereby, DOX can effectively reduce skin laceration after CCH treatment.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Oral doxycycline prevents skin-associated adverse effects induced by injectable collagenase in a rodent model of capsular contracture around silicone implants

et al. 2022

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“…Due to their ability to degrade specific cell-membrane or extracellular-matrix components, they play key roles in host colonization. They contribute to the spread of the pathogen into the host tissues, ensure the influx of proper nutrients for survival and growth, e.g., amino acids into the bacterial cells, and facilitate toxins' diffusion [14,15].…”

Section: Introductionmentioning

confidence: 99%

Candidates for Repurposing as Anti-Virulence Agents Based on the Structural Profile Analysis of Microbial Collagenase Inhibitors

et al. 2021

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The pharmacological inhibition of the bacterial collagenases (BC) enzymes is considered a promising strategy to block the virulence of the bacteria without targeting the selection mechanism leading to drug resistance. The chemical structures of the Clostridium perfringens collagenase A (ColA) inhibitors were analyzed using Bemis–Murcko skeletons, Murcko frameworks, the type of plain rings, and docking studies. The inhibitors were classified based on their structural architecture and various scoring methods were implemented to predict the probability of new compounds to inhibit ColA and other BC. The analyses indicated that all compounds contain at least one aromatic ring, which is often a nitrobenzene fragment. 2-Nitrobenzene based compounds are, on average, more potent BC inhibitors compared to those derived from 4-nitrobenzene. The molecular descriptors MDEO-11, AATS0s, ASP-0, and MAXDN were determined as filters to identify new BC inhibitors and highlighted the necessity for a compound to contain at least three primary oxygen atoms. The DrugBank database was virtually screened using the developed methods. A total of 100 compounds were identified as potential BC inhibitors, of which, 10 are human approved drugs. Benzthiazide, entacapone, and lodoxamide were chosen as the best candidates for in vitro testing based on their pharmaco-toxicological profile.

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“…(M9B subfamily) and Vibrio spp. (M9A subfamily) ( 13 ). These bacterial enzymes are capable of cleaving soluble and fibrillar collagen down into small peptides ( 14 – 16 ).…”

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confidence: 99%

A conserved strategy to attack collagen: The activator domain in bacterial collagenases unwinds triple-helical collagen

Serwanja,

Wieland,

Haubenhofer

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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Bacterial collagenases are important virulence factors, secreted by several pathogenic Clostridium , Bacillus , Spirochaetes , and Vibrio species. Yet, the mechanism by which these enzymes cleave collagen is not well understood. Based on biochemical and mutational studies we reveal that collagenase G (ColG) from Hathewaya histolytica recognizes and processes collagen substrates differently depending on their nature (fibrillar vs. soluble collagen); distinct dynamic interactions between the activator and peptidase domain are required based on the substrate type. Using biochemical and circular dichroism studies, we identify the presumed noncatalytic activator domain as the single-domain triple helicase that unwinds collagen locally, transiently, and reversibly.

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Inhibition and Activity Regulation of Bacterial Collagenases

Cited by 7 publications

References 148 publications

Oral doxycycline prevents skin-associated adverse effects induced by injectable collagenase in a rodent model of capsular contracture around silicone implants

Oral doxycycline prevents skin-associated adverse effects induced by injectable collagenase in a rodent model of capsular contracture around silicone implants

Candidates for Repurposing as Anti-Virulence Agents Based on the Structural Profile Analysis of Microbial Collagenase Inhibitors

A conserved strategy to attack collagen: The activator domain in bacterial collagenases unwinds triple-helical collagen

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