β-Lactamase Inhibitors Under Research

Abstract

The main modes of resistance to β-lactams are modification of cell targets (penicillin-binding proteins), impermeability of the cell wall, efflux, and production of inactivating enzymes, the β-lactamases. β-Lactamases are a complex family of enzymes, and currently more than 300 unique β-lactamases have been reported for gram-positive and gram-negative bacteria. Research on β-lactamases led to different classifications, one of which is the Ambler classification describing four classes: A, C, D (serine β-lactamases), and B (metalloprotease β-lactamases). β-Lactamase inhibitors can be divided globally into two groups: β-lactams and non-β-lactams. A number of compounds of clavulanic acid have been prepared to explore the structure-activity relationship. It was shown that (i) the lack of the C-4 carboxylic group does not eliminate the β-lactamase inhibitory activity and (ii) a catalytic group at position 2 enhances the inhibitory activity 4 to 10 times. Semisynthetic penicillanic derivatives such as halo penicillanic acid sulfones were designed to mimic the mechanism of enzyme inactivation observed with clavulanic acid. PS-5 is hydrolyzed by β-lactamases of B. cereus, Proteus vulgaris, C. freundii, and Streptomyces spp. Intensive research on β-lactamase inhibitors is needed: (i) enlarge the inhibitory spectrum to cover class C and class B enzymes, (ii) to overcome the rapid spread of ESBL, and (iii) to be prepared for an eventual reduction of activity of existing compounds, such as clavulanic acid.