| Alternating pattern of stereochemistry in the nonactin macrocycle is required for antibacterial activity and efficient ion binding. | |
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MedLine Citation:
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PMID: 19902940 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Nonactin is a polyketide antibiotic produced by Streptomyces griseus ETH A7796 and is an ionophore that is selective for K(+) ions. It is a cyclic tetraester generated from two monomers of (+)-nonactic acid and two of (-)-nonactic acid, arranged (+)-(-)-(+)-(-) so that nonactin has S4 symmetry and is achiral. To understand why achiral nonactin is the naturally generated diastereoisomer, we generated two alternate diastereoisomers of nonactin, one prepared solely from (+)-nonactic acid and one prepared solely from (-)-nonactic acid, referred to here as 'all-(+)-nonactin' and 'all-(-)-nonactin', respectively. Both non-natural diastereoisomers were 500-fold less active against gram positive organisms than nonactin confirming that the natural stereochemistry is necessary for biological activity. We used isothermal calorimetry to obtain the K(a), DeltaG, DeltaH, and DeltaS of formation for the K(+), Na(+), and NH(4)(+) complexes of nonactin and all-(-)-nonactin; the natural diastereoisomer bound K(+) 880-fold better than all-(-)-nonactin. A picrate partitioning assay confirmed that all-(-)-nonactin, unlike nonactin, could not partition K(+) ions into organic solvent. To complement the thermodynamic data we used a simple model system to show that K(+) transport was facilitated by nonactin but not by all-(-)-nonactin. Modeling of the K(+) complexes of nonactin and all-(-)-nonactin suggested that poor steric interactions in the latter complex precluded tight binding to K(+). Overall, the data show that both enantiomers of nonactic acid are needed for the formation of a nonactin diastereoisomer that can act as an ionophore and has antibacterial activity. |
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Authors:
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Brian R Kusche; Adrienne E Smith; Michele A McGuirl; Nigel D Priestley |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural |
Journal Detail:
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Title: Journal of the American Chemical Society Volume: 131 ISSN: 1520-5126 ISO Abbreviation: J. Am. Chem. Soc. Publication Date: 2009 Dec |
Date Detail:
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Created Date: 2009-11-25 Completed Date: 2010-01-21 Revised Date: 2011-03-03 |
Medline Journal Info:
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Nlm Unique ID: 7503056 Medline TA: J Am Chem Soc Country: United States |
Other Details:
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Languages: eng Pagination: 17155-65 Citation Subset: IM |
Affiliation:
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Department of Chemistry and Biochemistry, University of Montana, 32 Campus Drive, Missoula, Montana 59812-1656, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Anti-Bacterial Agents
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chemistry*,
pharmacology Gram-Negative Bacteria / drug effects Ions Macrocyclic Compounds / chemistry*, pharmacology Macrolides / chemistry Microbial Sensitivity Tests Stereoisomerism |
| Grant Support | |
ID/Acronym/Agency:
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AI072158/AI/NIAID NIH HHS; CA77347/CA/NCI NIH HHS; R01 CA077347-10/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Anti-Bacterial Agents; 0/Ions; 0/Macrocyclic Compounds; 0/Macrolides; 6833-84-7/nonactin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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