student profile: Ms Kenya Fernandes


Thesis work

Thesis title: Synergistic antifungal effects of lactoferrin in combination with amphotericin B

Supervisors: Dee CARTER , Joshua HO

Thesis abstract:

Due to the rising incidence of severe fungal infections, the discovery and development of novel antifungal compounds is more important than ever. Natural products represent a significant source of these compounds, and an increasing number are being identified from mammalian sources including milk proteins. Previous work in the Carter lab has shown that the multifunctional milk glycoprotein lactoferrin (Lf) acts synergistically with amphotericin B (AMB), the current gold-standard drug for antifungal treatment, reducing its minimum inhibitory concentration substantially. This is significant as amphotericin B is quite toxic and its use requires hospitalisation, monitoring, and is associated with severe side effects. The use of combination therapy in antifungal treatments is increasingly necessary, and the need for synergents that increase the efficacy of antifungal drugs is crucial. A wide spectrum of activity across yeasts and moulds have been reported for Lf and its derived peptides, some of which have potency surpassing that of the intact protein. However, considerable research is still required to understand the antifungal actions of these molecules, and their potential to support current antifungals such as AMB. In this study, a systematic evaluation of the potency of Lf and various derived peptides will be undertaken across numerous yeast, mould, and dermatophyte species incorporating reference, clinical, and drug resistant strains in order to determine and compare the spectrum of antifungal activity. The efficacy of synergistic treatment with Lf and AMB �em�in vivo�/em� will be then be tested using wax moth, and mucosal candidiasis infection models. Finally, the mechanistic basis of the antifungal action of Lf and significant peptides in synergy with AMB will be investigated by qPCR, flow cytometry and microscopy in the clinically relevant yeast �em�Candida glabrata�/em�, an increasingly significant opportunistic fungal pathogen due to its rapid development of antifungal drug resistance.

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