Interactions between penicillin-binding proteins (PBPs) and two novel classes of PBP inhibitors, arylalkylidene rhodanines and arylalkylidene iminothiazolidin-4-ones.
Several non-beta-lactam compounds were active against various gram-positive and gram-negative bacterial strains. The MICs of arylalkylidene rhodanines and arylalkylidene iminothiazolidin-4-ones were lower than those of ampicillin and cefotaxime for methicillin-resistant Staphylococcus aureus MI339 and vancomycin-resistant Enterococcus faecium EF12. Several compounds were found to inhibit the cell wall synthesis of S. aureus and the last two steps of peptidoglycan biosynthesis catalyzed by ether-treated cells of Escherichia coli or cell wall membrane preparations of Bacillus megaterium. The effects of the arylalkylidene rhodanines and arylalkylidene iminothiazolidin-4-one derivatives on E. coli PBP 3 and PBP 5, Streptococcus pneumoniae PBP 2xS (PBP 2x from a penicillin-sensitive strain) and PBP 2xR (PBP 2x from a penicillin-resistant strain), low-affinity PBP 2a of S. aureus, and the Actinomadura sp. strain R39 and Streptomyces sp. strain R61 DD-peptidases were studied. Some of the compounds exhibited inhibitory activities in the 10 to 100 microM concentration range. The inhibition of PBP 2xS by several of them appeared to be noncompetitive. The dissociation constant for the best inhibitor (Ki = 10 microM) was not influenced by the presence of the substrate.
Centre for Protein Engineering, University of Liège, Liège, Belgium.
Astrid
A
Zervosen
Wei-Ping
WP
Lu
Zhouliang
Z
Chen
Ronald E
RE
White
Thomas P
TP
Demuth
Jean-Marie
JM
Frère
D000465:Algorithms; D000475:Alkenes / Q000737:chemistry / Q000494:pharmacology*; D001410:Bacillus megaterium / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D001419:Bacteria / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D002473:Cell Wall / Q000187:drug effects / Q000378:metabolism; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors; D004926:Escherichia coli / Q000187:drug effects; D006602:Hexosyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D007700:Kinetics; D002267:Muramoylpentapeptide Carboxypeptidase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D046915:Penicillin-Binding Proteins; D010457:Peptidoglycan / Q000096:biosynthesis; D010458:Peptidyl Transferases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D011480:Protease Inhibitors / Q000494:pharmacology; D012236:Rhodanine / Q000737:chemistry / Q000494:pharmacology*; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*
D000475:Alkenes; D001426:Bacterial Proteins; D002352:Carrier Proteins; D046915:Penicillin-Binding Proteins; D010457:Peptidoglycan; D011480:Protease Inhibitors; D013844:Thiazoles; D012236:Rhodanine; D010458:Peptidyl Transferases; D006602:Hexosyltransferases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D002267:Muramoylpentapeptide Carboxypeptidase