The therapeutic use of beta-lactam antibiotics is being steadily hampered by the increasing prevalence of resistance mechanisms. Since beta-lactams are the first line of defence against infection and constitute over 50% of all antibiotics in clinical use, this global issue is of great concern.1 The spread of beta-lactamases that inactivate these safe antibiotics leads to a major reduction in efficacy of these proven treatments. An emerging threat are the AmpC class of beta-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.2 Since AmpC is often resistant to clinically available beta-lactamase inhibitors, new strategies for coping with bacterial resistance mechanisms are of current interest.
The expression of AmpC beta-lactamase within many of these resistant bacteria depends critically on the activity of a beta-N-acetylglucosaminidase known as NagZ,3 which acts to generate a peptidoglycan catabolite that interacts with a transcriptional regulator of the ampC gene. Under normal conditions, the ampC gene is not transcribed, but when beta-lactams are present, the level of this NagZ-produced catabolite rises and AmpC production is induced. Inhibitors of NagZ should block accumulation of the key peptidoglycan catabolite, therefore blocking production of AmpC, and rendering bacteria containing ampC susceptible to beta-lactams.
Here we describe the synthesis of a range of putative inhibitors of NagZ and assessment of their activity. 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.