Reversal of Fluconazole Resistance by Sulfated Sterols from the Marine Sponge <i>Topsentia</i> sp.

DiGirolamo, Jessica A.; Li, Xing-Cong; Jacob, Melissa R.; Clark, Alice M.; Ferreira, Daneel

doi:10.1021/np900177m

Cited by 56 publications

(35 citation statements)

References 24 publications

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“…[144]. The list of fungal EPIs is further expanded with the cyclic peptides unnarmicin A and unnarmicin C that were identified by testing a library of marine microorganisms [145] sulfated sterols from the marine sponge Topsentia sp [146], acridone derivatives [147] and ibuprofen [148]. …”

Section: Fungal Epismentioning

confidence: 99%

Microbial Efflux Pump Inhibition: Tactics and Strategies

Tegos

Haynes²,

Strouse³

et al. 2011

CPD

132

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Traditional antimicrobials are increasingly suffering from the emergence of multidrug resistance among pathogenic microorganisms. To overcome these deficiencies, a range of novel approaches to control microbial infections are under investigation as potential alternative treatments. Multidrug efflux is a key target of these efforts. Efflux mechanisms are broadly recognized as major components of resistance to many classes of chemotherapeutic agents as well as antimicrobials. Efflux occurs due to the activity of membrane transporter proteins widely known as Multidrug Efflux Systems (MES). They are implicated in a variety of physiological roles other than efflux and identifying natural substrates and inhibitors is an active and expanding research discipline. One plausible alternative is the combination of conventional antimicrobial agents/antibiotics with small molecules that block MES known as multidrug efflux pump inhibitors (EPIs). An array of approaches in academic and industrial research settings, varying from high-throughput screening (HTS) ventures to bioassay guided purification and determination, have yielded a number of promising EPIs in a series of pathogenic systems. This synergistic discovery platform has been exploited in translational directions beyond the potentiation of conventional antimicrobial treatments. This venture attempts to highlight different tactical elements of this platform, identifying the need for highly informative and comprehensive EPI-discovery strategies. Advances in assay development genomics, proteomics as well as the accumulation of bioactivity and structural information regarding MES facilitates the basis for a new discovery era. This platform is expanding drastically. A combination of chemogenomics and chemoinformatics approaches will integrate data mining with virtual and physical HTS ventures and populate the chemical-biological interface with a plethora of novel chemotypes. This comprehensive step will expedite the preclinical development of lead EPIs.

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Section: Fungal Epismentioning

confidence: 99%

Microbial Efflux Pump Inhibition: Tactics and Strategies

Tegos

Haynes²,

Strouse³

et al. 2011

CPD

132

View full text Add to dashboard Cite

show abstract

“…A limited number of small molecules have demonstrated modest potential in this arena, 6–11 and the proteins Hsp90 and calcineurin appear integral to some of the resistance pathways utilized by Candida . 12 This tentative progress towards stemming the increasing fluconazole resistance of Candida prompted us to screen the National Institutes of Health Molecular Libraries Probe Production Centers Network (NIH-MLPCN) compound collection with the goal of identifying small molecules that act as fungal-selective chemosensitizers and could be used to probe the various antifungal resistance mechanisms of Candida .…”

mentioning

confidence: 99%

Piperazinyl quinolines as chemosensitizers to increase fluconazole susceptibility of Candida albicans clinical isolates

Youngsaye

Vincent

Hartland

et al. 2011

Bioorganic & Medicinal Chemistry Letters

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The effectiveness of the potent antifungal drug fluconazole is being compromised by the rise of drug-resistant fungal pathogens. While inhibition of Hsp90 or calcineurin can reverse drug resistance in Candida, such inhibitors also impair the homologous human host protein and fungal-selective chemosensitizers remain rare. The MLPCN library was screened to identify compounds that selectively reverse fluconazole resistance in a Candida albicans clinical isolate, while having no antifungal activity when administered as a single agent. A piperazinyl quinoline was identified as a new small molecule probe satisfying these criteria.

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“…To our knowledge, only geodisterol [10] and two sulfated congeners [11] have been reported from marine sponges. One unusual feature of geodisterol among ring-A aromatized sterols is that the side chain is fully intact, whereas it is more common for the side chain to have undergone carbon-carbon bond cleavage, as in 1 and 2 .…”

mentioning

confidence: 99%