PhD defence for Lasse Kjellerup – Københavns Universitet

PhD defence for Lasse Kjellerup

The elements of antifungal drug discovery – from protons to zink

Fungal infections are estimated to cause 1.5 million death every year and new antifungal drugs with novel modes of actions are currently needed. I have explored two new types of antifungal inhibitors with potential as antifungal drugs.

The first new type of inhibitors target the plasma membrane proton ATPase (Pma1). Pma1 pumps protons out of the cell and thereby regulates the membrane potential and the intracellular pH. This enzyme is essential in fungal cells and as it is not present in humans, it is an obvious drug target. I have developed several methods for studying the effects of these inhibitors on fungal cells. Generally, these inhibitors decrease the membrane potential, decrease the intracellular pH, prevent proton pump mediated media acidification and a highly increased intracellular ATP content. Most of these traits were expected except from the increase in intracellular ATP. ATP is the energy source of Pma1 and the assay was primarily performed to exclude indirect inhibition of the pump. These inhibitors do however still require further optimization, before they can be potential drugs.

The second type of inhibitors targets the fungal zinc homeostasis. Zinc ions needs to be tightly controlled within the fungal cell as too low levels will inhibit zinc proteins from functioning and too high levels will cause inhibition of non-zinc proteins. The zinc homeostasis is also important in human cells, but we have observed that these inhibitors has a much stronger impact on fungal cells than human cells. One explanation for the preference for inhibiting fungal cells is a possible difference in how zinc signaling functions in these organisms. Zinc signaling is a well-known phenomenon in human cells, but has not previously been demonstrated within the fungal kingdom. I have however shown that zinc is mobilized within fungal cells in response to external stimuli and dependently on a well-known signaling pathway, strongly suggesting zinc as a signaling molecule within fungal cells as well. The inhibitors was further shown to be effective in an animal model, where they could treat mice with fungal infections and thereby highlighting these inhibitors as potential drugs for human patients in the future.

Supervisor

Anja Thoe Fuglsang, PLEN

Co-supervisor

Anne-Marie Lund Winther, Pcovery

Assessment committee

Professor Thomas Günther-Pomorski (Chair), PLEN
Associate Professor Peter Vangheluwe, Faculty of Medicine, KU Leuven, Belgium
Associate Professor Bjørn Panyella Pedersen, Aarhus University

Reception afterwards in M117-1 and K117-2. 
All are welcome!