Document Detail


The isotridecanyl side chain of plusbacin-A3 is essential for the transglycosylase inhibition of peptidoglycan biosynthesis.
MedLine Citation:
PMID:  23421534     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Plusbacin-A3 (pb-A3) is a cyclic lipodepsipeptide that exhibits antibacterial activity against multidrug-resistant Gram-positive pathogens. Plusbacin-A3 is thought not to enter the cell cytoplasm, and its lipophilic isotridecanyl side chain is presumed to insert into the membrane bilayer, thereby facilitating either lipid II binding or some form of membrane disruption. Analogues of pb-A3, [(2)H]pb-A3 and deslipo-pb-A3, were synthesized to test membrane insertion as a key to the mode of action. [(2)H]pb-A3 has an isotopically (2)H-labeled isopropyl subunit of the lipid side chain, and deslipo-pb-A3 is missing the isotridecanyl side chain. Both analogues have the pb-A3 core structure. The loss of antimicrobial activity in deslipo-pb-A3 showed that the isotridecanyl side chain is crucial for the mode of action of the drug. However, rotational-echo double-resonance nuclear magnetic resonance characterization of [(2)H]pb-A3 bound to [1-(13)C]glycine-labeled whole cells of Staphylococcus aureus showed that the isotridecanyl side chain does not insert into the lipid membrane but instead is found in the staphylococcal cell wall, positioned near the pentaglycyl cross-bridge of the cell-wall peptidoglycan. Addition of [(2)H]pb-A3 during the growth of S. aureus resulted in the accumulation of Park's nucleotide, consistent with the inhibition of the transglycosylation step of peptidoglycan biosynthesis.
Authors:
Sung Joon Kim; Manmilan Singh; Aaron Wohlrab; Tsyr-Yan Yu; Gary J Patti; Robert D O'Connor; Michael VanNieuwenhze; Jacob Schaefer
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2013-03-05
Journal Detail:
Title:  Biochemistry     Volume:  52     ISSN:  1520-4995     ISO Abbreviation:  Biochemistry     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-03-19     Completed Date:  2013-05-09     Revised Date:  2014-07-04    
Medline Journal Info:
Nlm Unique ID:  0370623     Medline TA:  Biochemistry     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1973-9     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Anti-Infective Agents / chemistry*,  metabolism,  pharmacology*
Bacteria / drug effects
Bacterial Infections / drug therapy
Depsipeptides / chemistry*,  metabolism,  pharmacology*
Enzyme Inhibitors / chemistry,  metabolism,  pharmacology
Humans
Peptidoglycan / metabolism*
Staphylococcal Infections / drug therapy,  microbiology
Staphylococcus aureus / drug effects*,  enzymology,  growth & development,  metabolism*
Grant Support
ID/Acronym/Agency:
AI059327/AI/NIAID NIH HHS; EB002058/EB/NIBIB NIH HHS; R01 AI059327/AI/NIAID NIH HHS; R01 EB002058/EB/NIBIB NIH HHS; R01 ES022181/ES/NIEHS NIH HHS
Chemical
Reg. No./Substance:
0/Anti-Infective Agents; 0/Depsipeptides; 0/Enzyme Inhibitors; 0/Peptidoglycan; 0/plusbacin A3
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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