β-Lactamase Inhibitors in Overcoming Bacterial Antibiotic Resistance

The widespread prevalence of antibiotic-resistant pathogenic microorganisms that cause infectious diseases in humans and animals severely limits the possibilities of chemotherapy. Large families of enzymes play a key role in the various mechanisms of bacterial antibiotic resistance; in particular, resistance to β-lactam antibiotics in Gram-negative pathogens is due to the production of β-lactamases involving serine hydrolases and metalloenzymes. Due to the high cost of developing new antibacterial drugs, the main approach to overcoming bacterial antibiotic resistance is to combine β-lactams with β-lactamase inhibitors. This review analyzes information about two generations of inhibitors of this superfamily of enzymes: first-generation inhibitors are structural analogs of β-lactams and inhibit only class A serine β-lactamases. Second-generation inhibitors include compounds of the diazabicyclooctane class and boronic acid derivatives. They form complexes with β-lactamases that mimic the structure of acyl-enzyme complexes with antibiotics or the structure of the transition state of these complexes. Second-generation inhibitors are characterized by broader inhibitory specificity compared to first-generation inhibitors. Derivatives of cyclic boronic acids (oxoborines) have the broadest specificity for serine and metallo-β-lactamases. The development of new combinations of antibiotics with inhibitors that target various β-lactamases will restore the therapeutic efficacy of β-lactam antibacterial agents.