Document Detail


Trihydroxamate siderophore-fluoroquinolone conjugates are selective sideromycin antibiotics that target Staphylococcus aureus.
MedLine Citation:
PMID:  23350642     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Siderophores are multidentate iron(III) chelators used by bacteria for iron assimilation. Sideromycins, also called siderophore-antibiotic conjugates, are a unique subset of siderophores that enter bacterial cells via siderophore uptake pathways and deliver the toxic antibiotic in a "Trojan horse" fashion. Sideromycins represent a novel antibiotic delivery technology with untapped potential for developing sophisticated microbe-selective antibacterial agents that limit the emergence of bacterial resistance. The chemical synthesis of a series of mono-, bis-, and trihydroxamate sideromycins are described here along with their biological evaluation in antibacterial susceptibility assays. The linear hydroxamate siderophores used for the sideromycins in this study were derived from the ferrioxamine family and inspired by the naturally occurring salmycin sideromycins. The antibacterial agents used were a β-lactam carbacepholosporin, Lorabid, and a fluoroquinolone, ciprofloxacin, chosen for the different locations of their biological targets, the periplasm (extracellular) and the cytoplasm (intracellular). The linear hydroxamate-based sideromycins were selectively toxic toward Gram-positive bacteria, especially Staphylococcus aureus SG511 (MIC = 1.0 μM for the trihydroxamate-fluoroquinolone sideromycin). Siderophore-sideromycin competition assays demonstrated that only the fluoroquinolone sideromycins required membrane transport to reach their cytoplasmic biological target and that a trihydroxamate siderophore backbone was required for protein-mediated active transport of the sideromycins into S. aureus cells via siderophore uptake pathways. This work represents a comprehensive study of linear hydroxamate sideromycins and teaches how to build effective hydroxamate-based sideromycins as Gram-positive selective antibiotic agents.
Authors:
Timothy A Wencewicz; Timothy E Long; Ute Möllmann; Marvin J Miller
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-02-14
Journal Detail:
Title:  Bioconjugate chemistry     Volume:  24     ISSN:  1520-4812     ISO Abbreviation:  Bioconjug. Chem.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-03-20     Completed Date:  2013-12-12     Revised Date:  2014-03-26    
Medline Journal Info:
Nlm Unique ID:  9010319     Medline TA:  Bioconjug Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  473-86     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Anti-Bacterial Agents / administration & dosage*,  chemistry,  metabolism
Drug Delivery Systems / methods*
Ferrous Compounds / administration & dosage*,  chemistry,  metabolism
Fluoroquinolones / administration & dosage*,  chemistry,  metabolism
Hydroxamic Acids / administration & dosage*,  chemistry,  metabolism
Microbial Sensitivity Tests
Peptides / administration & dosage*,  chemistry,  metabolism
Siderophores / administration & dosage*,  chemistry,  metabolism
Staphylococcus aureus / drug effects*,  metabolism
Grant Support
ID/Acronym/Agency:
T32 GM075762/GM/NIGMS NIH HHS; T32GM075762/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Anti-Bacterial Agents; 0/Ferrous Compounds; 0/Fluoroquinolones; 0/Hydroxamic Acids; 0/Peptides; 0/Siderophores; 56509-18-3/sideromycins
Comments/Corrections

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