Abstract
Tacrolimus (FK506) is an immunosuppressant drug widely used to avoid organ rejection in transplant patients. It has a profound influence on the cellular stress response by interfering with the calmodulin-calcineurin signaling pathway. In this context FK506 also became a valuable antifungal drug in medical care. Here it is shown in vitro that tacrolimus has a potent growth inhibition activity against 11 fungi and 3 oomycetes of agricultural importance. The significance of this finding is discussed with respect to crop protection. The in silico molecular docking to 6 major antifungal enzymes determined UDP-N-acetylmuramoyl-L-alanine: D-glutamate ligase (MurD) as the main target by the best affinity score.
Highlights
Azoles, echinocandines, pyrimidine analogs and polyenes are among the most common antifungals in human medical care and crop protection
Experimental evidence suggests that tacrolimus binds to the intracellular protein FKBP12 and thereby interferes with the calcineurin signal pathway, which is a key element in regulation of intracellular Ca2+ concentration.[4]
Strains of filamentous fungi were obtained from the following sources: Aspergillus niger DSM 246, Altenaria alternata DSM 1102, Fusarium equiseti DSM 21725, F. graminearum DSM 1095, F. fujikuroi DSM 893, Verticillium lecanii, Penicillium digitatum DSM 2731 from DSMZ (Braunschweig, Germany); Fusarium oxysporum 39/1201 St. 9336 and Botrytis cinerea from the Technische Universität Berlin (Germany); Colletotrichum higginsianum MAFF 305635, originally isolated in Japan, via the Department of Biology, Friedrich-Alexander-Universität (Erlangen, Germany); Phytophthora infestans GL-1 01/14 wild strain, p-3 (4/91; R+) and p-4 (4/91; R-) strains were kindly donated by Julius Kühn-Institut (Quedlinburg, Germany)
Summary
Echinocandines, pyrimidine analogs and polyenes are among the most common antifungals in human medical care and crop protection. The arise of fluconazole-resistant mutants among Cryptococcus neoformans clinical isolates was observed.[3] In search for new targets for antifungals the calmodulin-calcineurin signaling cascade came into focus. Experimental evidence suggests that tacrolimus binds to the intracellular protein FKBP12 and thereby interferes with the calcineurin signal pathway, which is a key element in regulation of intracellular Ca2+ concentration.[4] FKBP12-tacrolimus inhibits the phosphatase activity of the calmodulin-CnA-CnB complex, which in turn silences transcription factor Crz[1] and corresponding stress related genes. In combination with standard antifungal drugs FK506 may reverse resistance against them or increase their efficacy.[8,9] phytopathogenic fungi rely on the calcineurin pathway securing cell wall and membrane integrity, virulence[10] or formation of infectious appressoria.[11]. We describe novel antifungal efficacy of FK506 towards eleven pathogenic fungi and three Phytophthora oomycetes of agricultural importance
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
