Translation elongation-3-like factors: are they rational antifungal targets?
The occurrence of fungal infection has escalated significantly in recent years and is expected to continue to increase for the foreseeable future. Unfortunately, only a limited number of antifungal drugs are currently available partially due to a lack of suitable targets. The most commonly used antifungals target the same molecule in the cell membrane and, while efficacious, are either extremely toxic or susceptible to resistance. This article examines elongation factor-3, which is unique to fungi and essential for fungal cell survival and, thus, an attractive antifungal target. A search for inhibitors of this 'perfect target' led to identification of compounds (sordarins) which inhibited elongation factor-2, a protein with a mammalian homologue. Molecular analysis demonstrated why sordarins can specifically act against fungal elongation factor-2. This data questions the validity of pursuing genes as targets only if they are unique to fungi. Proteins that are homologous to elongation factor-3 are also discussed. The advances in molecular techniques and bioinformatics will allow the re-evaluation of targets previously thought to be unattractive. In addition, molecular genetics provides new and novel information on cellular processes that can potentially introduce new targets.
Sturtevant
Joy
J
Dept of Microbiology, Immunology and Parasitology, Center of Excellence in Oral and Craniofacial Biology, LSU Health Sciences Center - School of Dentistry, 1100 Florida Ave, Box F8-130, New Orleans, LA 70119, USA. jsturt@lsuhsc.edu
D000935:Antifungal Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002175:Candida / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D025141:Drug Resistance, Fungal; D005656:Fungal Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D018390:Gene Targeting; D006801:Humans; D009181:Mycoses / Q000188:drug therapy*; D020648:Peptide Elongation Factor 1 / Q000502:physiology; D010445:Peptide Elongation Factors / Q000037:antagonists & inhibitors* / Q000235:genetics; D010641:Phenotype; D011328:Prions / Q000187:drug effects; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D013045:Species Specificity
D000935:Antifungal Agents; D005656:Fungal Proteins; D020648:Peptide Elongation Factor 1; D010445:Peptide Elongation Factors; D011328:Prions; D029701:Saccharomyces cerevisiae Proteins; C111584:YEF3 protein, S cerevisiae