Interactions between Penicillin-Binding Proteins (PBPs) and Two Novel Classes of PBP Inhibitors, Arylalkylidene Rhodanines and Arylalkylidene Iminothiazolidin-4-ones

Abstract

Several non-␤-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 vancomycinresistant 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 DDpeptidases were studied. Some of the compounds exhibited inhibitory activities in the 10 to 100 M concentration range. The inhibition of PBP 2xS by several of them appeared to be noncompetitive. The dissociation constant for the best inhibitor (K i ‫؍‬ 10 M) was not influenced by the presence of the substrate.

Discovery of New Inhibitors of Resistant Streptococcus pneumoniae Penicillin Binding Protein (PBP) 2x by Structure-Based Virtual Screening

“…This can be done by measuring the initial rates of S2d hydrolysis near the K m value and up to 10 times the K m value in the presence of different inhibitor concentrations. 51 In the presence of the highest concentration of S2d that can be studied by spectrometry (i.e., 7 mM), a linear relationship between the initial rates and the substrate concentration was still observed. This indicated that it is only possible to determine the k cat /K m value of S2d (value equal to 350 ( 50 M -1 s -1 ) as described by others 52 but not to study the initial rates of S2d hydrolysis up to 10 times the K m value.…”

Resistance to ?-lactam antibiotics

“…Finally, given the therapeutic success of b-lactams, the search is now on for novel agents that also target PBPs (e.g. [386][387][388][389]). …”

One-Pot Synthesis of 5-Arylidene-2-Imino-4-Thiazolidinones under Microwave Irradiation

“…4-Thiazolidinone derivatives constitute an important class of heterocyclic compounds for their potential pharmaceutical applications [1][2][3][4][5][6][7][8]. Consequently, a large number of synthetic protocols leading to these compounds have been reported in the literature [9].…”