Synthetic Organotellurium Compounds Sensitize Drug-Resistant Candida albicans Clinical Isolates to Fluconazole.
Invasive Candida albicans infections are a serious health threat for immunocompromised individuals. Fluconazole is most commonly used to treat these infections, but resistance due to the overexpression of multidrug efflux pumps is of grave concern. This study evaluated the ability of five synthetic organotellurium compounds to reverse the fluconazole resistance of C. albicans clinical isolates. Compounds 1 to 4, at <10 μg/ml, ameliorated the fluconazole resistance of Saccharomyces cerevisiae strains overexpressing the major C. albicans multidrug efflux pumps Cdr1p and Mdr1p, whereas compound 5 only sensitized Mdr1p-overexpressing strains to fluconazole. Compounds 1 to 4 also inhibited efflux of the fluorescent substrate rhodamine 6G and the ATPase activity of Cdr1p, whereas all five of compounds 1 to 5 inhibited Nile red efflux by Mdr1p. Interestingly, all five compounds demonstrated synergy with fluconazole against efflux pump-overexpressing fluconazole-resistant C. albicans clinical isolates, isolate 95-142 overexpressing CDR1 and CDR2, isolate 96-25 overexpressing MDR1 and ERG11, and isolate 12-99 overexpressing CDR1, CDR2, MDR1, and ERG11 Overall, organotellurium compounds 1 and 2 were the most promising fluconazole chemosensitizers of fluconazole-resistant C. albicans isolates. Our data suggest that these novel organotellurium compounds inhibit pump efflux by two very important and distinct families of fungal multidrug efflux pumps: the ATP-binding cassette transporter Cdr1p and the major facilitator superfamily transporter Mdr1p.
Laboratório de Bioquímica Microbiana, Departamento de Microbiologia Geral, IMPG/CCS, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
L F
LF
Reis de Sá
Laboratório de Organocatálise e Síntese Orgânica, Instituto de Química, Departamento de Química Fundamental, Universidade de São Paulo, São Paulo, Brazil.
F T
FT
Toledo
Laboratório de Organocatálise e Síntese Orgânica, Instituto de Química, Departamento de Química Fundamental, Universidade de São Paulo, São Paulo, Brazil.
A C
AC
Gonçalves
Laboratório de Organocatálise e Síntese Orgânica, Instituto de Química, Departamento de Química Fundamental, Universidade de São Paulo, São Paulo, Brazil.
B A
BA
Sousa
Laboratório de Organocatálise e Síntese Orgânica, Instituto de Química, Departamento de Química Fundamental, Universidade de São Paulo, São Paulo, Brazil.
A A
AA
Dos Santos
Laboratório de Bioquímica Microbiana, Departamento de Microbiologia Geral, IMPG/CCS, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
P F
PF
Brasil
Laboratório de Bioquímica Microbiana, Departamento de Microbiologia Geral, IMPG/CCS, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
V A
VA
Duarte da Silva
Laboratório de Bioquímica Microbiana, Departamento de Microbiologia Geral, IMPG/CCS, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.|Instituto Federal de Educação, Ciência e Tecnologia, Rio de Janeiro, Brazil.
A C
AC
Tessis
Instituto Federal de Educação, Ciência e Tecnologia, Rio de Janeiro, Brazil.
J A
JA
Ramos
Instituto Federal de Educação, Ciência e Tecnologia, Rio de Janeiro, Brazil.
M A
MA
Carvalho
Department of Oral Sciences, Faculty of Dentistry, University of Otago, Dunedin, New Zealand.
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E
Lamping
Laboratório de Bioquímica Microbiana, Departamento de Microbiologia Geral, IMPG/CCS, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil apereira@micro.ufrj.br.
A
0000-0002-0474-8388
A
Ferreira-Pereira
D000935:Antifungal Agents / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D025141:Drug Resistance, Fungal / Q000235:genetics; D015725:Fluconazole / Q000494:pharmacology*; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects / Q000235:genetics; D008826:Microbial Sensitivity Tests; D015609:Organotechnetium Compounds / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism
D000935:Antifungal Agents; D005656:Fungal Proteins; D015609:Organotechnetium Compounds; D029701:Saccharomyces cerevisiae Proteins; D015725:Fluconazole
efflux pumps; multidrug resistance; organotellurium; yeasts