Abstract
The proliferation of pathogens expressing β-lactamases with extended spectrum and increased expression, decreased permeability and the presence of multiple β-lactamases in Gram-negative pathogens has compromised the empirical use of many β-lactam antibiotics, especially cephalosporins and now carbapenems. Theoretically, existing β-lactamase inhibitors could be used in combination with appropriate β-lactams to overcome resistance mediated by extended spectrum β-lactamases, but new β-lactamase inhibitors with broader spectra, including activity against Class C β-lactamases, should prove useful in combination with β-lactams, particularly cephalosporins or carbapenems, against problematic strains. To design and optimize inhibitors with broad enzyme inhibitory activity that will be useful in therapy, drug design must encompass, along with measures of enzyme inhibition, concomitant assessment of these inhibitors in synergizing selected β-lactams in whole cell antibacterial assays.