Targeting carbapenemases for fighting antibiotic-resistant Gram-negative bacteria

Coordinators : T. Naas, B. Iorga
Starting date: January 2012

Multidrug resistant (MDR) gram-negative pathogens, especially Enterobacteriaceae, are emerging worldwide. The MDR pattern is relatively common with resistance appearing to all major classes of anti-gram-negative agents (e.g. β-lactams, fluoroquinolones, and aminoglycosides), and in some cases, resistance to all available drugs. This is particularly worrisome in view of the current dearth of new compounds active against MDR gram-negatives in the pipeline.

β-Lactams, due to their safety, reliable killing properties and clinical efficacy, are among the most frequently prescribed antibiotics used to treat bacterial infections. However, their utility is being threatened by the worldwide proliferation of β-lactamases (BL) with broad hydrolytic capabilities, especially in MDR gram-negative bacteria. These BLs are divided into 4 classes based on their sequence identities. Currently, BL-mediated resistance does not spare even the newest and most powerfulβ-lactams (i.e. carbapenems), whose activity is challenged by the Metallo BLs (NDM, VIM, IMP) as well as the serine-carbapenemases (KPC, OXA-48). The dissemination of these enzymes amongEnterobacteriaceaeis a matter of concern: these pathogens are a major cause of nosocomial but also community-acquired infections, and carbapenems are key players in the treatment of these infections.

 Carbapenem resistance is increasing worldwide, especially in Klebsiellapneumoniae. In some countries such as Greece, it has already achieved the frightening rate of 45%, or as India massive spread of NDM-producers has been evidenced. In France the rate is still low, but new cases are identified weekly and several hospital outbreaks have been described.

 The development of new antibiotics is of low priority in the pharmaceutical industry and thus relies on academic research to find new targets and invent new antibiotics. Since the discovery of novel antibiotics with novel targets is difficult to foresee, inhibition strategies of carbapenemases may preserve our current armamentarium. Optimal combinations may require a ß-lactam with high stability to many common BLs together with one and possibly two BL inhibitors that can effectively inhibit both serine BLs and Metallo-BLs.

To achieve the overall objective of identifying new generations of BL inhibitors, we have assembled a team comprising expertise in cutting-edge medical microbiology, ß-lactam resistance mechanisms, medicinal chemistry, long-standing experience in β-lactam chemistry, structural biology, modeling and molecular dynamics simulations, high throughput screening, and virtual screening/molecular design.