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Riparin II-type benzamides as novel antibiofilm agents against dermatophytes: chemical synthesis, in vitro, ex vivo and in silico evaluation
Abstract Background The ability of dermatophytes to develop biofilms in host tissues confers physical and biochemical resistance to antifungal drugs. Therefore, research to find new compounds against dermatophyte biofilm is crucial. Objectives To evaluate the antifungal activity of riparin II (RIP2)...
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Published in: | Journal of antimicrobial chemotherapy 2024-03, Vol.79 (3), p.617-631 |
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Main Authors: | , , , , , , , , |
Format: | Article |
Language: | English |
Citations: | Items that this one cites |
Online Access: | Get full text |
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Summary: | Abstract
Background
The ability of dermatophytes to develop biofilms in host tissues confers physical and biochemical resistance to antifungal drugs. Therefore, research to find new compounds against dermatophyte biofilm is crucial.
Objectives
To evaluate the antifungal activity of riparin II (RIP2), nor-riparin II (NOR2) and dinor-riparin II (DINOR2) against Trichophyton rubrum, Microsporum canis and Nannizzia gypsea strains.
Methods
Initially, we determined the minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) of benzamides. We evaluated the inhibitory effects on the development of dermatophyte biofilms using in vitro and ex vivo models. Finally, we built three-dimensional models of the sulphite pump Ssu1 to investigate the interactions with the benzamides by molecular docking.
Results
RIP2 showed a broad spectrum of activity against T. rubrum, M. canis and N. gypsea, whereas NOR2 and DINOR2 were more selective. Furthermore, the shortening of the carbon chain from RIP2 benzamide to NOR2 and DINOR2 homologs caused a decrease in the MIC values. The benzamides reduced biofilm production and viability in vitro (P < 0.05) at MIC. This result was similar ex vivo in human nail fragments tests, but NOR2 and DINOR2 showed significant results at 2xMIC (P < 0.05). We constructed a model of the Ssu1 protein for each dermatophyte with high similarity. Molecular docking showed that the benzamides obtained higher binding energy values than ciclopirox.
Conclusions
Our study shows the antibiofilm potential for riparin II-type benzamides as new drugs targeting dermatophytes by inhibiting the Ssu1 protein. |
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ISSN: | 0305-7453 1460-2091 1460-2091 |
DOI: | 10.1093/jac/dkae013 |