Analysis of the effect of atorvastatin on the virulence of Fungal Pathogens

Fungal pathogens of humans cause harmful infections and can cause diverse diseases in humans which range from superficial skin infections to life-threatening diseases. The opportunistic pathogen Candida albicans causes a wide range of diseases primarily in immunocompromised individuals. Aspergillus fumigatus is a serious cause of disease in immune deficient patients or in those with pulmonary disease (e.g. cystic fibrosis (CF), asthma), and is the second most common opportunistic fungal pathogen of humans. Galleria mellonella larvae are an ideal model of infection to quickly and easily evaluate the virulence of a range of human fungal pathogens. Atorvastatin is a member of the statin drug family which are the main therapeutic agents used to decrease high serum cholesterol levels by inhibiting HMG-CoA reductase enzyme. HMG-CoA is an enzyme that is responsible for the production of farnesyl diphosphate which is the precursor for the production of cholesterol in humans and ergosterol in fungi. The aim of the work presented here was to analyse the antifungal activity of a widely prescribed statin (atorvastatin) and assess the effect of atorvastatin on the on the virulence of C. albicans and A. fumigatus. The study also investigated the effect of atorvastatin on G. mellonella larvae. The results obtained demonstrated that atorvastatin has anti-fungal activity and it reduced growth and viability of C. albicans and A. fumigatus. Exposure of C. albicans and A. fumigatus to this drug leads to the release of protein, amino acids and a reduction in ergosterol synthesis, and increased gliotoxin release in A. fumigatus. Proteomic analysis revealed increased abundance of proteins associated with an oxidative stress response, ergosterol biosynthesis and secondary metabolites. Atorvastatin can be used to inhibit the growth of C. albicans and A. fumigatus in G. mellonella larvae. Atorvastatin was shown to be non-toxic to G. mellonella larvae and not to induce an immune response when administered to larvae. The results presented in this thesis indicate that atorvastatin is non-toxic and capable of inhibiting the growth and virulence of C. albicans and A. fumigatus.

Name dc:type.qualificationname

phd

Level dc:type.qualificationlevel

doctoral

Grantor dc:publisher.institution

National University of Ireland Maynooth

Year dc:date.issued

2019

Author dc:creator

• Bashir Ajdidi, Ahmad

Language dc:language

en