ASSESSMENT OF ASPERGILLUS KINASES AS TARGETS FOR ANTIFUNGAL DRUG DISCOVERY

UoM administered thesis: Phd

  • Authors:
  • Narjes Al-Furaiji

Abstract

Fungi cause a wide range of infections with a significant increment in annual burden, and a total estimate of 1.5 million deaths per year, with over a billion being at risk was reported recently. Fungal treatments are limited to certain classes of drugs. However, undesirable side effects, drug–drug interactions and the toxicity associated with some classes and the emergence of resistance with others has limited their use; thus, new antifungal drugs are needed. Protein kinases constitute the second most common group of drug targets after G-protein-coupled receptors, since they regulate most aspects of cell life by phosphorylation. In this project, we aimed to explore the druggability of kinases in the human pathogen A. fumigatus, in an attempt to address the scarcity of known antifungal agents through the validation of completely novel drug targets that can overcome the problems associated with current antifungal drugs, particularly provoking the increasing emergence of antifungal drug resistance. Through a process of identification of protein kinases, 175 kinases were annotated in A. fumigatus A1163, identifying 15 filamentous fungal specific kinases, and other highly conserved kinases that share less than 50% similarity with humans, and they represent prospective antifungal targets. A high-throughput gene knockout strategy enabled the disruption of 115 PK genes, with 39 genes being identified as indispensable for viability; nine out of the total share 90% sequence similarity, while it shares

Details

Original languageEnglish
Awarding Institution
Supervisors/Advisors
Award date1 Aug 2020