Synthetic organotelluride compounds induce the reversal of Pdr5p mediated fluconazole resistance in Saccharomyces cerevisiae

Author(s)

Reis de Sa, Leandro Figueira ^[1] ; Toledo, Fabiano Travanca ^[2] ; de Sousa, Bruno Artur ^[2] ; Goncalves, Augusto Cesar ^[2] ; Tessis, Ana Claudia ^{[1, 3]} ; Wendler, Edison P. ^[2] ; Comasseto, Joao V. ^{[2, 4]} ; Dos Santos, Alcindo A. ^[2] ; Ferreira-Pereira, Antonio ^[1]

Affiliation

^[1] Univ Fed Rio de Janeiro, CCS, Inst Microbiol Paulo Goes, Dept Microbiol Geral, Lab Bioquim Microbiana, Rio De Janeiro, RJ - Brazil

^[2] Univ Sao Paulo, Inst Quim, Dept Quim Fundamental, Sao Paulo - Brazil

^[3] Inst Fed Educ Ciencia & Tecnol Rio De Janeiro IFR, Rio De Janeiro, RJ - Brazil

^[4] Univ Fed Sao Paulo UNIFESP, Inst Ciencias Ambientais Quim & Farmaceut, Sao Paulo - Brazil

• Document type: Journal article
• Source: BMC Microbiology; v. 14, JUL 26 2014.
• Web of Science Citations: 3

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 M 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 mu M. When tested at 100 mu M, 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. (AU)

• FAPESP's process: 08/55401-1 - Preparation and application of chiral compounds containing chalcogens
• Grantee: João Valdir Comasseto
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 12/17093-9 - A3-Coupling reactions on the synthesis of Codonopsinine and Monomorine I
• Grantee: João Luiz Petrarca de Albuquerque
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 11/11613-8 - A3-coupling reactions on the synthesis of bioactive nitrogen containing compounds
• Grantee: Alcindo Aparecido dos Santos
• Support Opportunities: Regular Research Grants
• FAPESP's process: 11/03244-2 - Asymmetric strategies in A-3 coupling eactions
• Grantee: Rafaela Costa Carmona
• Support Opportunities: Scholarships in Brazil - Master