Fungal Cell Wall Inhibitors: Emphasis on Clinical Aspects

Abstract

Invasive fungal infections, mainly caused by Candida and Aspergillus species, are an emerging cause of morbidity and mortality among all categories of immunocompromised patients. Currently available antifungal agents, both polyenes, flucytosine and (tri)azoles are hampered by serious infusion- or drug-related toxicity, by hazardous drug-drug interactions, or by pharmacokinetic problems and by the development of resistance, in vitro as well as in vivo. In recent years, several companies have become interested in antifungal drug development and have launched new compounds into preclinical and clinical trials. Some of these agents target the fungal cell wall in stead of the cell membrane. They exert their fungicidal action through inhibition of the synthesis of critical compounds of that fungal cell wall, not present in mammalian cells. Exciting and promising agents include inhibitors of beta-(1,3)-D-glucan synthase and inhibitors of chitin synthase. These drugs appear well tolerated in Phase I-II studies and will soon enter Phase III studies. This review wants to provide the clinical framework for assessing the utility of these agents compared to existing antifungals, thereby focusing on invasive fungal disease and emphasising the changing fungal epidemiology and susceptibility in immunocompromised hosts.

The use of standard methodology for determination of antifungal activity of natural products against medical yeasts Candida sp and Cryptococcus sp

“…These agents suffer from a number of limitations that can render their use complicated; for example, dose-limiting nephrotoxicity associated with Amphotericin B, rapid development of resistance with Flucytosine, drug-drug interactions, fungistatic mode of action and resistance development with the azoles. There is thus an urgent need for new antifungals with a broad fungicidal spectrum of action, and with fewer dose-limiting side effects (17,28). On the other hand, since natural products have been proven to be an excellent source of drugs, we need to find out new compounds with potential antifungal activity.…”

Two GDP-mannose transporters contribute to hyphal form and cell wall integrity in Aspergillus nidulans

“…One of the structures that differentiates a fungus from its host is the chitinous cell wall, which mediates many of the organism's interactions with its environment and regulates cell shape at all stages of development. An improved understanding of the fungal wall and of the processes that determine its integrity would add to our ability to control activities of fungal friends and foes (Maertens & Boogaerts, 2000). In addition to chitin and other polysaccharides, which play principally structural roles, a variety of proteins are also localized within cell walls (De Groot et al, 2005;Bowman & Free, 2006;Lesage & Bussey, 2006;Richard & Plaine, 2007).…”

Piperazine Propanol Derivative as a Novel Antifungal Targeting 1,3-.BETA.-D-Glucan Synthase

“…However, their clinical uses are restricted due to toxicity (polyenes), fungistatic activity (azoles), and the emergence of resistant isolates (azoles). 1,2) To overcome these problems, novel antifungal agents with a different mode of action are in demand.…”

“…In C. albicans, the catalytic and regulatory subunits are encoded by CaFKS1/GSC1, 11,12) and CaRHO1, 13) respectively. 1,3-b-D-Glucan synthase has three features of a promising target for an antifungal agent: 2,14,15) 1) its function is essential for growth, proven by the fact that the disruption of the genes for the catalytic subunit of 1,3-b-D-glucan synthase is a lethal event in S. cerevisiae, 6,8) C. albicans, 11,12) and Cryptococcus neoformans 16) ; 2) mammalian cells have no comparable cell wall, indicating that a 1,3-b-D-glucan synthase inhibitor would be highly selective to fungal cells; and 3) genes for catalytic subunits have been identified from several pathogenic fungi, such as C. albicans, 11,12) Cr. neoformans, 16) A. fumigatus, 17) and Paracoccidioides brasiliensis, 18) and are highly homologous to each other.…”