The therapeutic use of β-lactam antibiotics is being steadily eroded by the increasing prevalence of resistance mechanisms, and since β-lactams are the front line of defense against infection this development is of great concern. A newly emerging threat are the AmpC class of β-lactamases. Genes encoding AmpC are found in many Gram-negative bacteria including several opportunistic pathogens that show resistance to numerous antibiotics and cause life-threatening infections in immunocompromised patients. Due to the spread of AmpC and the fact that this enzyme is resistant to many clinically available β-lactamase inhibitors, new strategies for coping with this resistance mechanism are of current interest.

The production of AmpC β-lactamase within many of these organisms depends critically on the activity of an enzyme, known as NagZ, which acts to generate a peptidoglycan catabolite that then interacts with the transcriptional regulator of ampC. Under normal conditions the ampC gene is not transcribed however, when β-lactams are present the cellular concentration of this NagZ produced catabolite increases and AmpC production is stimulated.

Inhibitors of NagZ should block accumulation of the key peptidoglycan catabolite, thereby blocking the production of AmpC and rendering these bacteria once again susceptible to β-lactams. Here the rationale and evaluation of compounds as inhibitors of NagZ is discussed. Several potent and selective compounds are presented and a structural rationale for inhibitor potency and selectivity is also described. Furthermore, these inhibitors reduce the MIC values for several clinically relevant cephalosporins in both wild-type and AmpC hyper-producing bacterial strains in the presence of clinically relevant β-lactams. These compounds should prove useful in overcoming AmpC-mediated resistance in Gram-negative bacteria, and could lead to an effective treatment of otherwise dangerous antibiotic resistant bacterial infections.