Infectious diseases have recently attracted considerable attention on the LeadDiscovery website. This is because the anti-infectives market is poised to experience considerable growth in the next few years, with a forecast market value that is expected to double in size to more than $44 billion by 2010. This whole area is overviewed in one of our recently featured reports "Anti-Infectives 2002" (click here for access). Fungal infection is in particularly need of new treatments since there is not a single rapidly fungicidal, non-toxic drug available. Against this need is an increasing market. During the 1990's, the U.S. systemic antifungal market has grown 25% per year. Infections due to Candida account for about 80% of all major systemic fungal infections, and candida is now the fourth most prevalent organism found in bloodstream infections and is the most common cause of fungal infections in immunocompromised people. The frequency of nosocomial candidiasis has risen at least fivefold in the 1980s, making it one of the most common hospital-acquired infections. Although often a benign, self-limited problem, it may be associated with excess mortality of greater than 40% due to the development of candidiasis. The estimated health care cost of an episode of care for candidemia has been estimated to approximately $35,000 per Medicare patient. With roughly 30,000 patients falling victim to Candida nosocomial bloodstream infections per year, annual costs for just candidemia exceed $1bn (see another featured report "The Next Generation Antifungals: Triazoles vs. Peptides"). As reviewed in 'New Targets and Drug Discovery Platforms in Antifungal R&D' (click here for access), glycosylphosphatidylinositol anchoring, ABC phospholipid translocators, elongation factor-2 and calcineurin are all emerging as novel targets for the development of antifungals. An alternative approach to the improvement of antifungal treatment is the identification of molecules able to increase the efficacy or decrease the toxicity of existing drugs. Researchers at Drexel University College of Medicine have recently published data exemplifying this concept. The HDAC inhibitor, trichostatin A (TSA) dramatically increased the sensitivity of Candida albicans to the azoles fluconazole, itraconazole, and miconazole. Similar effects were observed with other HDA inhibitors and with the antifungals terbinafine and fenpropimorph, which target, as do azoles, enzymes in the ergosterol biosynthetic pathway. In contrast, HDA inhibitors had minimal effect on the activities of amphotericin B, flucytosine, and echinocandin, which have unrelated targets. Specifically, TSA lowered the MIC for five susceptible C. albicans isolates by more than 200-fold. TSA also enhanced itraconazole activity against Candida parapsilosis and Candida tropicalis but had no effect with four less related yeast species. This effect paralleled a dramatic decrease in the antifungal expression of ERG genes (encoding azole and terbinafine targets) and CDR/MDR1 genes (encoding multidrug transporters). The HDACs and their inhibitors have most commonly been discussed in relation to cancer (Click here to access "Histone deacetylase inhibitors: Redefining pharmaceutical approaches to the treatment of cancer") however, more recently we have focused on other therapeutic indication for molecules that modulate HDAC activity including asthma and now the growing field of antifungals

November, 2002

Adapted from Lamar Smith & Edlind, Antimicrobial Agents and Chemotherapy, November 2002, p. 3532-3539, Vol. 46, No. 11

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