title: Synthetic organotelluride compounds induce the reversal of Pdr5p mediated fluconazole resistance in Saccharomyces cerevisiae.
abstract: BACKGROUND
  Resistance to fluconazole, a commonly used azole antifungal, is a challenge for the treatment of fungal infections. Resistance can be mediated by overexpression of ABC transporters, which promote drug efflux that requires ATP hydrolysis. The Pdr5p ABC transporter of Saccharomyces cerevisiae is a well-known model used to study this mechanism of antifungal resistance. The present study investigated the effects of 13 synthetic compounds on Pdr5p.
  
  
  RESULTS
  Among the tested compounds, four contained a tellurium-butane group and shared structural similarities that were absent in the other tested compounds: a lateral hydrocarbon chain and an amide group. These four compounds were capable of inhibiting Pdr5p ATPase activity by more than 90%, they demonstrated IC50 values less than 2 μM and had an uncompetitive pattern of Pdr5p ATPase activity inhibition. These organotellurides did not demonstrate cytotoxicity against human erythrocytes or S. cerevisiae mutant strains (a strain that overexpress Pdr5p and a null mutant strain) even in concentrations above 100 μM. When tested at 100 μM, they could reverse the fluconazole resistance expressed by both the S. cerevisiae mutant strain that overexpress Pdr5p and a clinical isolate of Candida albicans.
  
  
  CONCLUSIONS
  We have identified four organotellurides that are promising candidates for the reversal of drug resistance mediated by drug efflux pumps. These molecules will act as scaffolds for the development of more efficient and effective efflux pump inhibitors that can be used in combination therapy with available antifungals.
authors: Leandro Figueira
authors: LF
authors: Reis de Sá
authors: Fabiano Travanca
authors: FT
authors: Toledo
authors: Bruno Artur
authors: BA
authors: de Sousa
authors: Augusto César
authors: AC
authors: Gonçalves
authors: Ana Claudia
authors: AC
authors: Tessis
authors: Edison P
authors: EP
authors: Wendler
authors: João V
authors: JV
authors: Comasseto
authors: Instituto de Microbiologia Paulo de Góes, Departamento de Microbiologia Geral, Laboratório de Bioquímica Microbiana, CCS, Universidade Federal do Rio de Janeiro, Rio de Janeiro/RJ, Brazil. alcindo@iq.usp.br.
authors: Alcindo A
authors: AA
authors: Dos Santos
authors: Antonio
authors: A
authors: Ferreira-Pereira
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000935:Antifungal Agents / Q000494:pharmacology*; D002073:Butanes / Q000378:metabolism / Q000633:toxicity; D025141:Drug Resistance, Fungal / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000378:metabolism*; D004912:Erythrocytes / Q000187:drug effects / Q000502:physiology; D015725:Fluconazole / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D013691:Tellurium / Q000378:metabolism* / Q000633:toxicity
chemical_list: D018528:ATP-Binding Cassette Transporters; D000935:Antifungal Agents; D002073:Butanes; D004791:Enzyme Inhibitors; C092438:PDR5 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C046888:butane; D015725:Fluconazole; D013691:Tellurium