Drug Target Discovery Through Analysis of Laccase Regulatory Networks of Cryptococccus neoformans

Peter   R.   Williamson; Shirong      Zhang; John      Panepinto; Guowu      Hu; Scott   R.   Waterman; Yoon-Dong      Park; Soowan      Shin

doi:10.2174/157340808786733640

Abstract

Opportunistic fungal infections are a growing problem as larger populations have become immunocompromised due to chemotherapy, organ transplant conditioning or infections such as HIV. Traditional approaches to identify drug targets in fungi are often focused on essential genes that are either not present in their mammalian host or differ sufficiently to allow chemotherapeutic discrimination. A complementary approach involves exploration of pathways involved in virulence (the so-called ‘virulome’), to identify potential ‘weak links,’ essential to successful infection by the pathogen. As an example, we will summarize work identifying virulence determinants within regulatory networks of the fungal pathogen, Cryptococccus neoformans. C. neoformans, is a fungal pathogen afflicting large numbers of AIDSrelated patients, and has become the most common cause of meningitis in the developing world. Molecular dissection of pathways related to the virulence factor laccase has identified cellular processes that are particularly important during infection including copper acquisition and phospholipid metabolism. Molecular analyses of these pathways have identified genetic predictions of infectious outcomes of cryptococcosis in organ transplant patients and has suggested novel synergistic drug combinations. These analyses may thus identify potential pathways sensitive to pharmacological intervention.

Keywords: Cryptococcus, fungus, drug design, regulation, virulence, clinical outcome, biological markers, clinical markers, laccase