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

BMC Genomics

Research Article

Maria Sueli S Felipe¹  Erika S Kioshima¹  Marcus M Teixeira¹  Ana Karina R Abadio²  Natalia F Martins³  Bernard Maigret⁴ 

[1] Department of Cellular Biology, University of Brasília, Brasília, Brazil;Department of Cellular Biology, University of Brasília, Brasília, Brazil;Lorrain Laboratory of Computing Research and its Applications, University Henri Poincaré-Nancy I, Nancy, France;Embrapa - Genetic Resources and Biotechnology, Brasília, Brazil;Lorrain Laboratory of Computing Research and its Applications, University Henri Poincaré-Nancy I, Nancy, France;

关键词: Homology Modeling;    Posaconazole;    Micafungin;    Anidulafungin;    Potential Drug Target;   

DOI  :  10.1186/1471-2164-12-75

 received in 2010-08-26, accepted in 2011-01-27,  发布年份 2011

来源: Springer

【 摘 要 】

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.

【 授权许可】

Unknown   
© Abadio et al; licensee BioMed Central Ltd. 2011. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.