These compounds that are expected to exhibit metal-binding characteristics were found to exhibit a time-dependent inhibition mechanism which fits a kinetic mechanism that is consistent with slow binding to the active site and even slower release of the inhibitor without expulsion of the metal ions form the MBL active site. More specifically, 6-phosphonomethylpyridine-2-carboxylates (PMPCs) and a number of derivatives thereof, synthesized previously in this research group have been shown in this thesis research to be potent inhibitors (low to submicromolar Ki) of the major Class B1 MBLs, IMP-1, VIM-2, NDM-1 and SPM-1 as well as the Class B3 MBL L1, all of which are dizinc enzymes, and somewhat less potent inhibitors of the monozinc Class B2 MBL, SFH-1, which is of lesser clinical significance. Some of these substrates also offer more favourable kinetic properties for assaying MBLs in vivo.Īlso in this thesis, biochemical as well as microbiological investigations of several classes of SBL and MBL inhibitors are describes as well as one class of cephalosporins that exhibit inhibition of MBLs and surprising antibacterial potency against certain clinically significant MBL-producing Gram negative bacteria. As a consequence of the increasing prevalence of resistance, there is much interest in the discovery of inhibitors for such clinically important β-lactamases as well as in the discovery of β-lactam antibiotics that are less susceptible to inactivation by β-lactamases.ĭescribed in this thesis are the kinetic properties of new chromogenic cephalosporin-type substrates that are susceptible to hydrolysis by clinically important SBLs and MBLs but that exhibit a much more pronounced colour change upon hydrolysis than does the commercially available and widely used chromogenic cephalosporin called nitrocefin.
Bacteria producing β-lactamases that are capable of hydrolyzing the β-lactam bond in all of the classes of β-lactam antibiotics including penicillins, monobactams, cephalosporins and carbapenems are of great clinical concern. Three of the classes of β-lactamases (classes A, C and D) are serine-β-lactamases (SBLs) and the fourth class (Class B) consists of metallo-β-lactamases (MBLs) that rely on one or two zinc ions for their catalytic activity. Resistance to these has evolved in a few different ways, notably by regulating permeability and by the expression of β-lactamases which hydrolyze the antibiotic before it reaches its target.
The majority of antibiotics prescribed for treatment of bacterial infections are β-lactam antibiotics.
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