Sordarins: A New Class of Antifungals with Selective Inhibition of the Protein Synthesis Elongation Cycle in Yeasts

Domínguez, Juan M.; Kelly, Valerie A.; Kinsman, Oonagh S.; Marriott, M. S.; Heras, F. G. De Las; Martin, J.J.

doi:10.1128/aac.42.9.2274

Cited by 116 publications

(46 citation statements)

References 21 publications

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“…The inhibition occurs without affecting the protein synthesis machinery in mammals [112]. The mechanism of action of sordarins appears to involve the inhibition of EF-2 [113]. The structure-affinity relationship for binding to EF-2 from different species is influenced by the nature of the sugar residue of the glycoside.…”

Section: Fungal Nucleic Acid and Protein Biosynthesis As A Drug Develmentioning

confidence: 99%

The Mechanistic Targets of Antifungal Agents: An Overview

Mazu¹,

Bricker²,

Flores‐Rozas³

et al. 2016

MRMC

162

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Pathogenic fungi are a major causative group for opportunistic infections (OIs). AIDS patients and other immunocompromised individuals are at risk for OIs, which if not treated appropriately, contribute to the mortality associated with their conditions. Several studies have indicated that the majority of HIV-positive patients contract fungal infections throughout the course of their disease. Similar observations have been made regarding the increased frequency of bone marrow and organ transplants, the use of antineoplastic agents, the excessive use of antibiotics, and the prolonged use of corticosteroids among others. In addition, several pathogenic fungi have developed resistance to current drugs. Together these have conspired to spur a need for developing new treatment options for OIs. To aid this effort, this article reviews the biological targets of current and emerging drugs and agents that act through these targets for the treatment of opportunistic fungal infections.

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Section: Fungal Nucleic Acid and Protein Biosynthesis As A Drug Develmentioning

confidence: 99%

The Mechanistic Targets of Antifungal Agents: An Overview

Mazu¹,

Bricker²,

Flores‐Rozas³

et al. 2016

MRMC

162

View full text Add to dashboard Cite

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“…Recent work has been directed toward the characterization of natural and semi-synthetic derivatives of sordarin [9,12,14,15,18], and Odds [19] has published an excellent review on the topic. Other examples of the many diverse structures reported recently include the azasordarin derivative shown in (2) which contains a morpholino group in place of the natural product's sugar moiety [14].…”

Section: Introductionmentioning

confidence: 99%

Improvement of sordarin production through process optimization: combining traditional approaches with DOE

Tully

Bergum

Schwarz

et al. 2006

J Ind Microbiol Biotechnol

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BMS-353645, also known as sordarin, was of interest based on its activity against pathogenic fungi. The objective of these studies was to provide high quality starting substrate for chemical modification aimed at further improving biological activity, with particular interest in the inhibition of Aspergillus. In the work presented here, Design of Experiments, or DOE, was successfully combined with traditional approaches to significantly improve sordarin yields in fermentation flasks. Overall, yields were increased 25-fold from <100 microg/g to as high as 2,609 microg/g in flasks through the use of various medium and conduction changes supplemented with DOE. The improved process was then successfully scaled to pilot plant tanks with the best batch producing 2,389 microg/g sordarin at the 250-l scale.

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“…Cellular mass was retained on cellulose filter paper (Whatman, Kent, UK), washed twice with DEPC-H 2 O and lysis buffer (8.5% (w/v) mannitol, 30 mM Hepes-KOH (pH 7.4), 100 mM potassium acetate, 2 mM magnesium acetate, 2 mM DTT), and finally resuspended in an equal volume of this buffer supplemented with 1 mM PMSF. The cells were broken by grinding with glass beads and an S-100 fraction was prepared as previously described (8). The material was passed through Sephadex G-25 (using a PD-10 column as described by the manufacturer) just before being used to remove low-molecular-weight components; this step was omitted if the presence of endogenous protein synthesis inhibitors was going to be tested.…”

Section: Methodsmentioning

confidence: 99%