|
rdf:type |
|
|
lifeskim:mentions |
|
|
pubmed:issue |
2
|
|
pubmed:dateCreated |
2005-1-27
|
|
pubmed:abstractText |
Penicillin-binding proteins (PBPs) catalyze the essential reactions in the biosynthesis of cell wall peptidoglycan from glycopeptide precursors. beta-Lactam antibiotics normally interfere with this process by reacting covalently with the active site serine to form a stable acyl-enzyme. The design of novel beta-lactams active against penicillin-susceptible and penicillin-resistant organisms will require a better understanding of the molecular details of this reaction. To that end, we compared the affinities of different beta-lactam antibiotics to a modified soluble form of a resistant Enterococcus faecium PBP5 (Delta1-36 rPBP5). The soluble protein, Delta1-36 rPBP5, was expressed in Escherichia coli and purified, and the NH(2)-terminal protein sequence was verified by amino acid sequencing. Using beta-lactams with different R1 side chains, we show that azlocillin has greater affinity for Delta1-36 rPBP5 than piperacillin and ampicillin (apparent K(i) = 7 +/- 0.3 microM, compared to 36 +/- 3 and 51 +/- 10 microM, respectively). Azlocillin also exhibits the most rapid acylation rate (apparent k(2) = 15 +/- 4 M(-1) s(-1)). Meropenem demonstrates an affinity for Delta1-36 rPBP5 comparable to that of ampicillin (apparent K(i) = 51 +/- 15 microM) but is slower at acylating (apparent k(2) = 0.14 +/- 0.02 M(-1) s(-1)). This characterization defines important structure-activity relationships for this clinically relevant type II transpeptidase, shows that the rate of formation of the acyl-enzyme is an essential factor determining the efficacy of a beta-lactam, and suggests that the specific side chain interactions of beta-lactams could be modified to improve inactivation of resistant PBPs.
|
|
pubmed:grant |
|
|
pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/15673741-12222968,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15673741-12389036,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15673741-12456788,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15673741-12543674,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15673741-12591921,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15673741-14534312,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15673741-3128280,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15673741-5219821,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15673741-7850204,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15673741-8759860,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15673741-9449253,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15673741-9614969,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15673741-9841666
|
|
pubmed:language |
eng
|
|
pubmed:journal |
|
|
pubmed:citationSubset |
IM
|
|
pubmed:chemical |
|
|
pubmed:status |
MEDLINE
|
|
pubmed:month |
Feb
|
|
pubmed:issn |
0066-4804
|
|
pubmed:author |
|
|
pubmed:issnType |
Print
|
|
pubmed:volume |
49
|
|
pubmed:owner |
NLM
|
|
pubmed:authorsComplete |
Y
|
|
pubmed:pagination |
612-8
|
|
pubmed:dateRevised |
2009-11-18
|
|
pubmed:meshHeading |
pubmed-meshheading:15673741-Acylation,
pubmed-meshheading:15673741-Algorithms,
pubmed-meshheading:15673741-Anti-Bacterial Agents,
pubmed-meshheading:15673741-Azlocillin,
pubmed-meshheading:15673741-Binding Sites,
pubmed-meshheading:15673741-Carbapenems,
pubmed-meshheading:15673741-Drug Resistance, Bacterial,
pubmed-meshheading:15673741-Enterococcus faecium,
pubmed-meshheading:15673741-Kinetics,
pubmed-meshheading:15673741-Models, Molecular,
pubmed-meshheading:15673741-Penicillin G,
pubmed-meshheading:15673741-Penicillin-Binding Proteins,
pubmed-meshheading:15673741-Peptidyl Transferases,
pubmed-meshheading:15673741-Plasmids,
pubmed-meshheading:15673741-Structure-Activity Relationship,
pubmed-meshheading:15673741-Thienamycins
|
|
pubmed:year |
2005
|
|
pubmed:articleTitle |
Structure-activity relationships of different beta-lactam antibiotics against a soluble form of Enterococcus faecium PBP5, a type II bacterial transpeptidase.
|
|
pubmed:affiliation |
Louis Stokes Cleveland Veterans Affairs Medical Center, 10701 East Blvd., Cleveland, OH 44106, USA.
|
|
pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, U.S. Gov't, Non-P.H.S.,
Research Support, Non-U.S. Gov't
|
