title: ERG2 and ERG24 Are Required for Normal Vacuolar Physiology as Well as Candida albicans Pathogenicity in a Murine Model of Disseminated but Not Vaginal Candidiasis.
abstract: Several important classes of antifungal agents, including the azoles, act by blocking ergosterol biosynthesis. It was recently reported that the azoles cause massive disruption of the fungal vacuole in the prevalent human pathogen Candida albicans. This is significant because normal vacuolar function is required to support C. albicans pathogenicity. This study examined the impact of the morpholine antifungals, which inhibit later steps of ergosterol biosynthesis, on C. albicans vacuolar integrity. It was found that overexpression of either the ERG2 or ERG24 gene, encoding C-8 sterol isomerase or C-14 sterol reductase, respectively, suppressed C. albicans sensitivity to the morpholines. In addition, both erg2Δ/Δ and erg24Δ/Δ mutants were hypersensitive to the morpholines. These data are consistent with the antifungal activity of the morpholines depending upon the simultaneous inhibition of both Erg2p and Erg24p. The vacuoles within both erg2Δ/Δ and erg24Δ/Δ C. albicans strains exhibited an aberrant morphology and accumulated large quantities of the weak base quinacrine, indicating enhanced vacuolar acidification compared with that of control strains. Both erg mutants exhibited significant defects in polarized hyphal growth and were avirulent in a mouse model of disseminated candidiasis. Surprisingly, in a mouse model of vaginal candidiasis, both mutants colonized mice at high levels and induced a pathogenic response similar to that with the controls. Thus, while targeting Erg2p or Erg24p alone could provide a potentially efficacious therapy for disseminated candidiasis, it may not be an effective strategy to treat vaginal infections. The potential value of drugs targeting these enzymes as adjunctive therapies is discussed.
authors.affiliation: Department of Microbiology, Immunology and Parasitology, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA Department of Clinical Pharmacy, Division of Clinical and Experimental Therapeutics, College of Pharmacy, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA.
authors.forename: Arturo
authors.initials: A
authors.lastname: Luna-Tapia
authors.affiliation: Department of Clinical Pharmacy, Division of Clinical and Experimental Therapeutics, College of Pharmacy, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA Department of Prosthodontics, School of Dentistry, LSU Health Sciences Center, New Orleans, Louisiana, USA.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Peters
authors.affiliation: Department of Physiology, Louisiana State University Health Sciences Center, School of Medicine, New Orleans, Louisiana, USA.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Eberle
authors.affiliation: Department of Microbiology, Immunology and Parasitology, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA.
authors.forename: Morgan E
authors.initials: ME
authors.lastname: Kerns
authors.affiliation: Department of Microbiology, Immunology and Parasitology, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Foster
authors.affiliation: Department of Medicine, Louisiana State University Health Sciences Center, School of Medicine, New Orleans, Louisiana, USA.
authors.forename: Luis
authors.initials: L
authors.lastname: Marrero
authors.affiliation: Department of Prosthodontics, School of Dentistry, LSU Health Sciences Center, New Orleans, Louisiana, USA.
authors.forename: Mairi C
authors.initials: MC
authors.lastname: Noverr
authors.affiliation: Department of Oral and Craniofacial Biology, School of Dentistry, LSU Health Sciences Center, New Orleans, Louisiana, USA.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Fidel
authors.affiliation: Department of Microbiology, Immunology and Parasitology, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA Department of Clinical Pharmacy, Division of Clinical and Experimental Therapeutics, College of Pharmacy, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA gpalmer5@uthsc.edu.
authors.forename: Glen E
authors.initials: GE
authors.lastname: Palmer
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects / Q000472:pathogenicity*; D058365:Candidiasis, Invasive / Q000382:microbiology / Q000473:pathology*; D002181:Candidiasis, Vulvovaginal / Q000382:microbiology / Q000473:pathology*; D043402:Cathepsin A / Q000378:metabolism; D025141:Drug Resistance, Fungal / Q000235:genetics; D004875:Ergosterol / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D005656:Fungal Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D025301:Hyphae / Q000235:genetics / Q000254:growth & development; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D009025:Morpholines / Q000494:pharmacology*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000235:genetics*; D013251:Steroid Isomerases / Q000037:antagonists & inhibitors / Q000235:genetics*; D014617:Vacuoles / Q000187:drug effects / Q000502:physiology*
chemical_list: D000935:Antifungal Agents; D005656:Fungal Proteins; D009025:Morpholines; D010088:Oxidoreductases; C022672:delta(14)-sterol reductase; D043402:Cathepsin A; D013251:Steroid Isomerases; C022669:delta(8)-delta(7)-sterol isomerase; D004875:Ergosterol