Title: Identification and mode of action analysis of new antibiofilm compounds against the fungal pathogen Candida albicans
Other Titles: Identificatie en analyse van het werkingsmechanisme van nieuwe antibiofilmcomponenten tegen de schimmelpathogeen Candida albicans
Authors: Delattin, Nicolas
Issue Date: 27-Oct-2014
Abstract: The incidence of human invasive fungal infections by opportunistic fungal pathogens has significantly increased during the past decade. One of the main reasons for this is the increasing number of immunocompromised patients due to HIV and immunosuppressive drugs in cancer therapy. In these immunocompromised patients invasive fungal infections are associated with very high mortality rates, ranging from 20-90%. Candida albicans is the most significant human fungal pathogen, followed by Aspergillus and Cryptococcus spp. One of the most important virulence traits of these pathogens is their ability to form biofilms, a highly ordered multicellular community of cells surrounded by a self-produced protective film of polysaccharides attached to a biotic or abiotic surface. Compared to planktonic, free-living cells, these biofilms show an increased tolerance to the human immune system and towards the currently used antifungal agents in the hospital. Moreover, biofilm formation is considered critical in the development and clinical outcome of fungal infections. Besides biofilm formation within the human host, Candida spp. are able to form biofilms on various abiotic surfaces of medical devices like catheters, voice prostheses, dentures, implants, etc., being an important source of (chronic) infections. Because of the increasing use of implants and other medical devices, partially due to the ageing population, the burden of biofilm-associated device infections is expected to increase significantly the next decades. Therefore, there is an urgent need for new compounds with specific antibiofilm activity. Furthermore, such new antibiofilm compounds can also be further developed into anti-infective coatings for medical devices. The above-mentioned clinical needs are the main goals of this PhD research.Experimental results of this doctoral thesis consist mainly of three parts describing the identification and study of the antibiofilm mode of action of three newly identified antibiofilm compounds, namely the small molecule toremifene and two peptides, OSIP108 and AS10. Additionally, another new family of small molecules with antibiofilm activity (BEC-2, i.e. minimal concentration of compounds resulting in 50% eradication of biofilm cells, ≥ 25 µM) was identified, the 2,6-disubstituted quinolines, but was not selected for further research.Toremifene belongs to the family of estrogen receptor modulators used in the treatment of breast and prostate cancer. Toremifene is a valuable example of the concept of drug repurposing, in which drugs known for their applications in specific medical domains are evaluated for their potential use in other applications. Toremifene is characterized in this doctoral study as a broad-spectrum antibiofilm agent with activity in vitro against biofilm formation of several Candida spp. (BIC-2, i.e. the minimal concentration of compounds resulting in 50% inhibition of biofilm formation ≥ 20 µM) and bacterial spp. and in vivo againstbiofilm formation of C. albicans in a subcutaneous rat catheter biofilm-associated infection model. Toremifene reduced biofilm formation on subcutaneously implanted catheters with 56% compared to the control treatment in the latter model after oral administration. In addition, toremifene is a strong potentiator of the classical antifungal agents, caspofungin and amphotericin B to a lesser extent, against C. albicans and C. glabrata biofilms. Toremifene reduced the effective dosages of the latter agents against these biofilms with 20- and 4-fold, respectively. Furthermore, toremifene inhibited C. albicans biofilm formation with 70% in a controlled release coating model system for implants, which was developed in collaboration with the Department of Materials Engineering of the KU Leuven. The second and third part of this work was dedicated to the identification and characterization of two new antibiofilm peptides, OSIP108 and AS10, isolated from plant and mouse, respectively. Both peptides show specific antibiofilm activity against C. albicans, (BIC-2 = 5 and 0.2 µM respectively), without affecting viability of the cells, which is an advantage over the classical fungicidal antifungal agents for which resistance is already described. In addition, both peptides are able to reduce the effective dosages of caspofungin and amphotericin B against mature C. albicans biofilms up to 8- and 5-fold, respectively. In contrast to OSIP108, AS10 is further characterised by antibiofilm activity against several bacterial spp. (BIC-2 ≥ 3 µM) and mixed bacterial-fungal biofilms. Preliminary results demonstrate the importance of the yeast-to-hypha transition and cell wall related processes in the antibiofilm mode of action of OSIP108 whereas the antibiofilm activity of AS10 seems to be linked to the white-to-opaque switch of C. albicans. In summary, results of this doctoral research contribute to the search for new antibiofilm compounds, which are urgently needed to reduce the high mortality rates of biofilm-associated device infections. In this respect, toremifene is a lead compound, which can be a valuable alternative for the classical antifungal agents in combating biofilm-associated device infections as it can be administered orally.
ISBN: 978-90-8826-379-8
Publication status: published
KU Leuven publication type: TH
Appears in Collections:Centre of Microbial and Plant Genetics

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