Screening for amino acid substitutions in the Candida albicans Erg11 protein of azole-susceptible and azole-resistant clinical isolates: new substitutions and a review of the literature

Morio, Florent; Logé, Cédric; Besse, Bernard; Hennequin, Christophe; Pape, Patrice Le

doi:10.1016/j.diagmicrobio.2009.11.006

Cited by 233 publications

(245 citation statements)

References 38 publications

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“…Their contribution to fluconazole resistance is still uncertain and requires further study. Single mutations of D116E, K128T, E266D, V437I or V488I may not contribute to azole resistance because they were found in both azole-resistant and azole-susceptible strains (Marichal et al, 1999;Morio et al, 2010;Perea et al, 2001;Sanglard et al, 1998;Ying et al, 2013). The novel V332L mutation was detected in nine strains, three of which were azole-resistant (33.33 %), two were S-DD (22.22 %) and four were azole-susceptible (44.44 %); therefore we suggest that V332L mutation probably does not contribute to azole resistance.…”

Section: Discussionmentioning

confidence: 99%

Genetic and phenotypic characterization of Candida albicans strains isolated from infectious disease patients in Shanghai

et al. 2015

Journal of Medical Microbiology

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Candida albicans, as an opportunistic pathogen, can cause superficial and life-threatening candidiasis in immunocompromised individuals. The formation of surface-associated biofilms and the appearance of drug resistance pose a significant challenge for clinical intervention. In this study, a total of 104 hospital-acquired C. alibcans clinical isolates were collected from sterile sites and mucosal lesions of 92 infectious disease patients in the Shanghai Public Health Clinical Center and analysed. The resistance rates to fluconazole, itraconazole and voriconazole were 12.5 %, 15.4 % and 11.5 % respectively. Multilocus sequence typing (MLST) analysis identified 63 diploid sequence types (DSTs) with a decentralized phylogeny, of which 37 DSTs (58.7 %) had not been reported in the online MLST database. Loss of heterozygosity was observed in ACC1 and ADP1 sequences obtained from six sequential isolates from a patient receiving antifungal treatment, which exemplified the effect of microevolution on C. albicans genetic alterations. Biofilm formation capability, an important virulence trait of C. albicans, was variable among strains isolated from different anatomical sites (P50.0302) and affected by genotypes (P50.0185). The mRNA levels of the azole antifungal target ERG11 gene and efflux pump genes (CDR1, CDR2 and MDR1) were detected in 9-18.1 % of azole-resistant and susceptible-dose dependent (S-DD) isolates. Twelve mutations encoding distinct amino acid substitutions in ERG11 were found in azoleresistant and S-DD isolates. Among them, A114S, Y132H and Y257H substitution in the ERG11 gene may be primarily related to azole resistance. Taken together, we observed a high level of diversity within C. albicans isolates. Multiple inter-related underlying mechanisms, including genetic and environmental factors, may account for high surface adhesion or azole resistance in clinical C. albicans infections.Abbreviations: AAT1, aspartate aminotransferase; ACC1, Acetyl-coenzyme A carboxylase; ACT1, actin; ADP1, ATP-dependent permease; ALS, hyphaspecific surface protein; BSI, nosocomial bloodstream infection; CDR1, CDR2, ATP-dependent efflux pumps; CLSI, Clinical and Laboratory Standard Institute; DST, diploid sequence type; ERG11, cytochrome P450 14a-demethylase; HWP1, hypha-specific cell wall protein; MDR1, major facilitator pump; MLST, multilocus sequence typing; MPI, mannose phosphate isomerase; SAP, secreted aspartyl protease; S-DD, susceptible-dose dependent; SYA1, alanyl-RNA synthetase; VPS13, vacuolar protein sorting protein; XTT, 2,3-bis-(2-methoxy-4-nitro-5-sulphenyl)-2H-tetrazolium-5-carboxanilide; YPD, yeast extract, peptone, dextrose medium; ZWF1b, glucose-6-phosphate dehydrogenase.

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Section: Discussionmentioning

confidence: 99%

Genetic and phenotypic characterization of Candida albicans strains isolated from infectious disease patients in Shanghai

et al. 2015

Journal of Medical Microbiology

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“…Amino acid sequences were downloaded from NCBI GenBank and annotated with reported amino acid substitutions8, 12, 13, 14, 15 using Geneious 6.1.8 software (Biomatters). Alignments of sequences were generated using the ClustalW16 algorithm with Blosum scoring matrix, gap opening penalty 10, gap extension penalty 0.5 and free end gaps.…”

Section: Note On the Alignmentsmentioning

confidence: 99%

Proposal for a unified nomenclature for target‐site mutations associated with resistance to fungicides

Mair

Lopez‐Ruiz

Stammler³

et al. 2016

Pest Management Science

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Evolved resistance to fungicides is a major problem limiting our ability to control agricultural, medical and veterinary pathogens and is frequently associated with substitutions in the amino acid sequence of the target protein. The convention for describing amino acid substitutions is to cite the wild‐type amino acid, the codon number and the new amino acid, using the one‐letter amino acid code. It has frequently been observed that orthologous amino acid mutations have been selected in different species by fungicides from the same mode of action class, but the amino acids have different numbers. These differences in numbering arise from the different lengths of the proteins in each species. The purpose of the present paper is to propose a system for unifying the labelling of amino acids in fungicide target proteins. To do this we have produced alignments between fungicide target proteins of relevant species fitted to a well‐studied ‘archetype’ species. Orthologous amino acids in all species are then assigned numerical ‘labels’ based on the position of the amino acid in the archetype protein. © 2016 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

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“…7,8 Dentre os principais mecanismos de resistência conhecidos em espécies de Candida estão: superexpressão de bombas de efluxo, diminuindo o acúmulo intracelular do fármaco; alterações na afinidade entre os derivados azólicos e alvo macromolecular, em decorrência de mutações envolvendo o gene ERG11, o qual codifica a enzima lanosterol 14a desmetilase.…”

Section: Introductionunclassified

“…6 Em função da ampla utilização desses medicamentos, observa-se uma redução na eficácia e aparecimento de cepas resistentes. 7,8 Dentre os principais mecanismos de resistência conhecidos em espécies de Candida estão: superexpressão de bombas de efluxo, diminuindo o acúmulo intracelular do fármaco; alterações na afinidade entre os derivados azólicos e alvo macromolecular, em decorrência de mutações envolvendo o gene ERG11, o qual codifica a enzima lanosterol 14a desmetilase. [9][10][11][12] Como alternativa para superar esses problemas estão sendo desenvolvidos novos derivados azólicos ativos contra cepas resistentes.…”

Section: Introductionunclassified

Estudos de QSAR 2D baseados em descritores topológicos e fragmentos moleculares para uma série de derivados azólicos ativos contra Candida albicans

2012

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Recebido em 29/3/11; aceito em 5/9/11; publicado na web em 30/9/11 2D-QSAR STUDIES BASED ON TOPOLOGICAL DESCRIPTORS AND MOLECULAR FRAGMENTS FOR A SERIES OF AZOLE DERIVATIVES ACTIVE AGAINST Candida albicans. Azole derivatives are the main therapeutical resource againstCandida albicans infection in immunocompromised patients. Nevertheless, the widespread use of azoles has led to reduced effectiveness and selection of resistant strains. In order to guide the development of novel antifungal drugs, 2D-QSAR models based on topological descriptors or molecular fragments were developed for a dataset of 74 molecules. The optimal fragment-based model (r 2 = 0.88, q 2 = 0.73 and r 2 pred = 0.62 with 6PCs) and descriptor-based model (r 2 = 0.82, q 2 = 0.79 and r 2 pred = 0.70 with 2 PCs), when analysed synergically, suggested that the triazolone ring and lipophilic properties are both important to antifungal activity.Keywords: antifungal; azole derivatives; QSAR. INTRODUÇÃODurante as últimas duas décadas, o risco de infecções causadas pela levedura patogênica C. albicans tornou-se cada vez mais comum, especialmente em pacientes imunocomprometidos.1-3 Por exemplo, cerca de 90% dos pacientes com HIV têm pelo menos um episódio de candidíase oral, cujo tratamento pode gerar gastos superiores a 55 mil dólares por pessoa. 4,5 Os fármacos de escolha para tratamento dessa infecção pertencem à classe dos derivados azólicos, que exercem sua função biológica através da inibição competitiva da enzima lanosterol 14a desmetilase (CYP51).6 Em função da ampla utilização desses medicamentos, observa-se uma redução na eficácia e aparecimento de cepas resistentes. 7,8 Dentre os principais mecanismos de resistência conhecidos em espécies de Candida estão: superexpressão de bombas de efluxo, diminuindo o acúmulo intracelular do fármaco; alterações na afinidade entre os derivados azólicos e alvo macromolecular, em decorrência de mutações envolvendo o gene ERG11, o qual codifica a enzima lanosterol 14a desmetilase.9-12 Como alternativa para superar esses problemas estão sendo desenvolvidos novos derivados azólicos ativos contra cepas resistentes.Estratégias de planejamento baseado na estrutura do alvo terapêu-tico são amplamente utilizadas pelas grandes indústrias farmacêuticas para identificar moléculas protótipo cuja potência e seletividade devem ser otimizadas através da satisfação de exigências estéreas e eletrônicas presentes apenas no alvo macromolecular.1,13 Entretanto, essa abordagem é limitada pela ausência de informações estruturais da enzima lanosterol 14a-desmetilase de C. albicans.14 A fim de contornar essa restrição, técnicas de modelagem por homologia têm sido empregadas.14,15 Contudo, a baixa identidade sequencial entre as proteínas molde e a proteína alvo, aproximadamente 30%, impede que informações detalhadas sobre a disposição espacial dos resíduos-chave para o reconhecimento molecular sejam identificadas de forma inequívoca. 16 desenvolveram modelos de QSAR 2D, por regressão linear múltipla, que destacam a capacidade de descri...

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Screening for amino acid substitutions in the Candida albicans Erg11 protein of azole-susceptible and azole-resistant clinical isolates: new substitutions and a review of the literature

Cited by 233 publications

References 38 publications

Genetic and phenotypic characterization of Candida albicans strains isolated from infectious disease patients in Shanghai

Genetic and phenotypic characterization of Candida albicans strains isolated from infectious disease patients in Shanghai

Proposal for a unified nomenclature for target‐site mutations associated with resistance to fungicides

Estudos de QSAR 2D baseados em descritores topológicos e fragmentos moleculares para uma série de derivados azólicos ativos contra Candida albicans

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