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Chapter 24 : Insights in Antifungal Drug Discovery
Category: Fungi and Fungal Pathogenesis; Clinical Microbiology
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This chapter is divided into two sections. The first section focuses on clinical perspectives, especially of global candidiasis. The second section discusses antifungal drug discovery by offering two different but interacting approaches: traditional, or classical, and genomic. A large study was recently published on a 10.5-year surveillance of susceptibility of Candida species to fluconazole and voriconazole. This study reported a slight trend toward an increasing resistance, in some regions, of NAC species like Candida tropicalis and Candida parapsilosis. In human immunodeficiency virus (HIV)/AIDS patients especially, mucosal candidiasis, or oropharyngeal candidiasis (OPC), remains one of the most common types of infection throughout the world, but especially in both adult and pediatric age groups in developing countries. Information on the incidence of vulvovaginal candidiasis (VVC) is incomplete as it is not reportable. However, the estimate is that VVC caused by Candida species affects about 70 to 75% of young women of childbearing age (most frequent); 40 to 50% of these individuals will have a recurrence, and 5 to 8% will develop recurrent VVC, defined as four or more episodes per year. Systemic candidiasis and bloodstream infections (BSI) also qualify as global infectious diseases. An increased incidence of invasive candidiasis (IC), aspergillosis, and zygomycosis has been reported in tertiary care facilities in India. The currently used echinocandins (caspofungin, micafungin, and anidulafungin) are still relatively new, and studies relating to their in vivo efficacy are ongoing.
The two pathways to antifungal drug discovery. The traditional, or classical, pathway starts with compound libraries that screen a panel of fungal species. Compounds are selected as fungicidal or fungistatic, optimized for activity, and tested for in vitro toxicity, and the best lead optimized compounds are selected. Genomic approaches start with deletion sets of mutants that can provide full coverage of the genome or partial sets (as for example, growth essential genes). The deletion sets are referred to as HIP or HOP (from HI profiling or homozygous deletion profiling, respectively), reflecting the nature of the set of mutants. Mutants of genes of interest are screened against compound libraries to identify hit compounds (left-pointing diagonal arrow). Or, compounds identified by classical methods are used against sets of mutants to identify the genetic target(s) (right-pointing diagonal arrow). MFC, minimal fungicidal concentration. doi:10.1128/9781555817176.ch24.f1
Integration of approaches, including macromolecular synthesis inhibition, microarray (MA), deletion sets (HI profiling [HIP] and homozygous deletion profiling [HOP]), and overexpression screens (OE) to identify targets of new drugs. The genes that belong to common areas in the diagram indicate the probable target(s) of a specific compound. The asterisk indicates that genetic mutants were identified from various screens. doi:10.1128/9781555817176.ch24.f2
The use of interaction profiles in determining active scaffolds and drug targets. A specific phenotypic interaction between gene “g” and compound “c” is used as the basis for this interaction profile. Compounds that have high coinhibition scores with compound c and other compounds that have the same phenotypic interaction with gene g are compared for structural relatedness to identify active scaffolds or possible target sites. Similarly, genes that have high cofitness scores with gene g and other genes that have the same phenotypic interaction with compound c are compared to look for functional relatedness to identify target genes or pathways. Also, the interaction between compounds with high coinhibition scores with compound c and gene g is evaluated. Similarly, the interaction between genes that have high cofitness scores with gene g and compound c can be determined (dotted arrows). doi:10.1128/9781555817176.ch24.f3