Structure-based drug development of new antifungals

The increasing emergence of multi-drug-resistant microorganisms has led the World Health Organisation to plead for action against antimicrobial resistance (AMR). In order to control the spread of infectious diseases is critical that new classes of antimicrobial agents with novel mechanisms of action are developed. In particular, fungal infections are now a very serious threat to health and human welfare. About 1.7 billion people worldwide are afflicted by fungal diseases. The majority of these infections are superficial, but a significant proportion are invasive infections, which are ostensibly difficult to treat and lead to an estimated 1.5 million deaths each year. This exceeds mortality estimates for either tuberculosis or malaria. The majority of this mortality is caused by Aspergillus and Candida species. Worryingly a growing and significant proportion of fungal infections are classified as being resistant. Therefore there is a desperate need for new antifungal drugs before the limited number of antifungal agents become ineffective.

This project aims to develop novel antifungal agents with novel mechanisms of action that will address this unmet medical need and the problems of intrinsic and acquired resistance blighting existing therapies. We have identified an essential enzyme for the growth of Candida albicans and Aspergillus fumigatus, which constitutes an attractive target for antifungal therapy. Recently we have determined the crystal structure of this enzyme and used it as model for computational screening of compound libraries. The hits obtained will be the starting point for further rounds of medicinal chemistry and structure-based drug design to develop new drugs.

This multidisciplinary project brings together expertise in fungal microbiology (Bromley), structure-based drug design (Tabernero), and organic and medicinal chemistry (Procter) to provide an exciting new approach to the treatment of antifungal resistance, a major health threat. The successful candidate will benefit from a diverse and enriching environment and will be trained in a number of key core skills: protein production, enzyme kinetics, structural biology, computational chemical biology and synthetic chemistry in combination with microbiological techniques. These skills will provide the student with a competitive advantage for future professional jobs in academia or industry and to become a research leader.

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in Biochemistry or Organic Chemistry. Candidates with experience in Medicinal Chemistry or Structural Biology and interest in Microbiology are particularly encouraged to apply.