Comparative genomics allowed the identification of drug targets against human fungal pathogens

Abstract

BackgroundThe prevalence of invasive fungal infections (IFIs) has increased steadily worldwide in the last few decades. Particularly, there has been a global rise in the number of infections among immunosuppressed people. These patients present severe clinical forms of the infections, which are commonly fatal, and they are more susceptible to opportunistic fungal infections than non-immunocompromised people. IFIs have historically been associated with high morbidity and mortality, partly because of the limitations of available antifungal therapies, including side effects, toxicities, drug interactions and antifungal resistance. Thus, the search for alternative therapies and/or the development of more specific drugs is a challenge that needs to be met. Genomics has created new ways of examining genes, which open new strategies for drug development and control of human diseases.ResultsIn silico analyses and manual mining selected initially 57 potential drug targets, based on 55 genes experimentally confirmed as essential for Candida albicans or Aspergillus fumigatus and other 2 genes (kre2 and erg6) relevant for fungal survival within the host. Orthologs for those 57 potential targets were also identified in eight human fungal pathogens (C. albicans, A. fumigatus, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Paracoccidioides lutzii, Coccidioides immitis, Cryptococcus neoformans and Histoplasma capsulatum). Of those, 10 genes were present in all pathogenic fungi analyzed and absent in the human genome. We focused on four candidates: trr1 that encodes for thioredoxin reductase, rim8 that encodes for a protein involved in the proteolytic activation of a transcriptional factor in response to alkaline pH, kre2 that encodes for α-1,2-mannosyltransferase and erg6 that encodes for Δ(24)-sterol C-methyltransferase.ConclusionsOur data show that the comparative genomics analysis of eight fungal pathogens enabled the identification of four new potential drug targets. The preferred profile for fungal targets includes proteins conserved among fungi, but absent in the human genome. These characteristics potentially minimize toxic side effects exerted by pharmacological inhibition of the cellular targets. From this first step of post-genomic analysis, we obtained information relevant to future new drug development.

pH Signaling in Human Fungal Pathogens: a New Target for Antifungal Strategies

“…While multiple targets can be envisioned to inhibit the Pac/Rim pathway, targets that are both well conserved in pathogenic fungi and are fungus specific should be prioritized (25,28,99,146). Fungus-specific components of the Pac/Rim pathways in pathogenic yeasts and fungi need to be fully characterized, both from a genetic and a biochemical point of view, in terms of mutant phenotype, protein structure, subcellular localization, and interactions.…”

Computational Identification of Putative Drug Targets in Malassezia Globosa by Subtractive Genomics and Protein Cluster Network Approach

“…A study showed that 57 potential drug targets from eight human fungal pathogens (Candida albicans, Aspergillus fumigatus, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Paracoccidioides lutzii, Coccidioides immitis, Cryptococcus neoformans and Histoplasma capsulatum), which did not include Malassezia sp., of which only 10 were conserved as essential targets [45].…”

Evolutionary Perspectives on Human Fungal Pathogens

“…Comparative genomics can also have a very practical side. A search for 55 genes essential to C. albicans or A. fumigatus found that ten were also found in other pathogens and that six of these were absent from humans; four of these are now the subject of pharmaceutical research (Abadio et al 2011).…”