Class C 3-lactamases

The functionalized phenaceturates 16 (Fig. 11.10) are substrates of class A and C [3-lactamases, especially the class C enzymes, as observed with the parent unfunctionalized phenaceturates 15. They are also modest inhibitors of these enzymes and the serine DD-peptidase of Streptomyces R61. The inhibition of class C [3-lactamases is turnover dependent, as expected for a mechanism-based inhibitor. Inhibition is not very dependent on the nature of the leaving group, suggesting that the QM is generated in solution after the product phenol has been released from the active site. It therefore... 

All these 3,4-dihydro-2H-1 -benzopyran-2-ones 17 and 18 are substrates of class A and class C (3-lactamases. They are thus the first 8-lactones that are hydrolyzed by [3-lactamases. The kcat values for these substrates are generally smaller than those of the analogous acyclic phenaceturates suggesting that the tethered leaving group obstructs the attack of water on the acyl-enzyme. Despite the apparent advantage of the long-lived acyl-enzymes, the irreversible inhibition by the functionalized compounds is no better than that of acyclic molecules 16. Thus, even the tethered QM cannot efficiently trap a second nucleophile at the [3-lactamase active site, at least as placed as dictated by the structure of compounds 18.70... 

Furthermore, the 3D-location of Tyr150 is quite different from that of Glu166 in class-A /3-lactamases. The observed resistance of the methoxylated cephalosporins to class-C /3-lactamases is due to a slow deacylation step [35], This inhibition is the result of the formation of an acyl-enzyme intermediate... 

Y. Kato-Toma, M. Ishiguro, Reaction of Lys-Tyr-Lys Triad Mimics with Benzylpenicil-lin Insight into the Role of Tyrl50 in Class C /3-Lactamase , Bioorg. Med. Chem. Lett. 2001, 11, 1161-1164. 

The examples discussed above constitute a selection of recent applications of the acid and basic hydrolysis of (3-lactams in synthesis. Hydrolysis and alcoholysis of (3-lactams can also be effected under roughly neutral reaction conditions when enzymes are the promoters [47]. The (3-lactamases catalyzed hydrolysis of (3-lactams is an efficient process for a broad spectrum of substrates, including those (3-lactams with base or acid sensitive groups [12-14]. This process proceeds through an acyl enzyme intermediate to give ring opened (3-amino acids. The class C (3-lactamases in particular, in Scheme 9, have the ability to catalyze the alcoholysis reaction and hence (3-amino esters are the products formed. 

Scheme 59 Inhibition of class C /3-lactamase via the formation of dihydro-1,4-thiazepine ring.

Hata M, Tanaka Y, Fujii Y, Neya S, Hoshino T (2005) A theoretical study on the substrate deacylation mechanism of class C [3-lactamase. J. Phys. Chem. B 109 16153-16160... 

Class C )3-Lactamase Citrobacter freundii 1982 Class A /3-Lactamase RTEM-3 ... 

Since (3-lactamases catalyze hydrolysis of p-lactams and thence are responsible for the loss of their antibiotic activity, a series of aryl and aryl-methyl (3-aryl- (3-ketophosphonates has been prepared as potential (3-lactamase inhibitors.These compounds, among them (240)-(243) were most effective against the class D OXA-1 (3-lactamase and the class C (3-lactamase of Enterobacter cloacae P99, but had a lesser activity against the OXA-10 enzyme and the class A TEM-2 enzyme, respectively. Reduction of the keto group to form the corresponding p-hydroxypho-sphonates led to a reduced inhibitory activity. 

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