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

• Main Authors: Martins Natalia F, Teixeira Marcus M, Kioshima Erika S, Abadio Ana Karina R, Maigret Bernard, Felipe Maria Sueli S
• Format: Article
• Language: English
• Published: BMC 2011-01-01
• Series: BMC Genomics
• Online Access: http://www.biomedcentral.com/1471-2164/12/75

<p>Abstract</p> <p>Background</p> <p>The 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.</p> <p>Results</p> <p><it>In silico </it>analyses and manual mining selected initially 57 potential drug targets, based on 55 genes experimentally confirmed as essential for <it>Candida albicans </it>or <it>Aspergillus fumigatus </it>and other 2 genes (<it>kre2 </it>and <it>erg6</it>) relevant for fungal survival within the host. Orthologs for those 57 potential targets were also identified in eight human fungal pathogens (<it>C. albicans</it>, <it>A. fumigatus</it>, <it>Blastomyces dermatitidis</it>, <it>Paracoccidioides brasiliensis</it>, <it>Paracoccidioides lutzii, Coccidioides immitis</it>, <it>Cryptococcus neoformans </it>and <it>Histoplasma capsulatum</it>). Of those, 10 genes were present in all pathogenic fungi analyzed and absent in the human genome. We focused on four candidates: <it>trr1 </it>that encodes for thioredoxin reductase, <it>rim8 </it>that encodes for a protein involved in the proteolytic activation of a transcriptional factor in response to alkaline pH, <it>kre2 </it>that encodes for α-1,2-mannosyltransferase and <it>erg6 </it>that encodes for Δ(24)-sterol C-methyltransferase.</p> <p>Conclusions</p> <p>Our 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.</p>