Dataset Information

ML212: A small-molecule probe for investigating fluconazole resistance mechanisms in Candida albicans.

ABSTRACT: The National Institutes of Health Molecular Libraries and Probe Production Centers Network (NIH-MLPCN) screened >300,000 compounds to evaluate their ability to restore fluconazole susceptibility in resistant Candida albicans isolates. Additional counter screens were incorporated to remove substances inherently toxic to either mammalian or fungal cells. A substituted indazole possessing the desired bioactivity profile was selected for further development, and initial investigation of structure-activity relationships led to the discovery of ML212.

SUBMITTER: Youngsaye W

PROVIDER: S-EPMC3740683 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Publications

ML212: A small-molecule probe for investigating fluconazole resistance mechanisms in Candida albicans.

Youngsaye Willmen W Hartland Cathy L CL Morgan Barbara J BJ Ting Amal A Nag Partha P PP Vincent Benjamin B Mosher Carrie A CA Bittker Joshua A JA Dandapani Sivaraman S Palmer Michelle M Whitesell Luke L Lindquist Susan S Schreiber Stuart L SL Munoz Benito B

Beilstein journal of organic chemistry 20130726

The National Institutes of Health Molecular Libraries and Probe Production Centers Network (NIH-MLPCN) screened >300,000 compounds to evaluate their ability to restore fluconazole susceptibility in resistant Candida albicans isolates. Additional counter screens were incorporated to remove substances inherently toxic to either mammalian or fungal cells. A substituted indazole possessing the desired bioactivity profile was selected for further development, and initial investigation of structure-ac ...[more]

PMID: 23946849

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Project description:Resistance to azole antifungals continues to be a significant problem in the common fungal pathogen Candida albicans. Many of the molecular mechanisms of resistance have been defined with matched sets of susceptible and resistant clinical isolates from the same strain. Mechanisms that have been identified include alterations in the gene encoding the target enzyme ERG11 or overexpression of efflux pump genes including CDR1, CDR2, and MDR1. In the present study, a collection of unmatched clinical isolates of C. albicans was analyzed for the known molecular mechanisms of resistance by standard methods. The collection was assembled so that approximately half of the isolates were resistant to azole drugs. Extensive cross-resistance was observed for fluconazole, clotrimazole, itraconazole, and ketoconazole. Northern blotting analyses indicated that overexpression of CDR1 and CDR2 correlates with resistance, suggesting that the two genes may be coregulated. MDR1 overexpression was observed infrequently in some resistant isolates. Overexpression of FLU1, an efflux pump gene related to MDR1, did not correlate with resistance, nor did overexpression of ERG11. Limited analysis of the ERG11 gene sequence identified several point mutations in resistant isolates; these mutations have been described previously. Two of the most common point mutations in ERG11 associated with resistance, D116E and E266D, were tested by restriction fragment length polymorphism analysis of the isolates from this collection. The results indicated that the two mutations occur frequently in different isolates of C. albicans and are not reliably associated with resistance. These analyses emphasize the diversity of mechanisms that result in a phenotype of azole resistance. They suggest that the resistance mechanisms identified in matched sets of susceptible and resistant isolates are not sufficient to explain resistance in a collection of unmatched clinical isolates and that additional mechanisms have yet to be discovered.

Dataset Information

ML212: A small-molecule probe for investigating fluconazole resistance mechanisms in Candida albicans.

Publications

ML212: A small-molecule probe for investigating fluconazole resistance mechanisms in Candida albicans.

Similar Datasets

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