The inhibition of extended spectrum β-lactamases: hits and leads.

The ongoing emergence of bacterial strains resistant to even third- and fourth-generation β-lactam antibiotics is one of the most pressing and challenging issues in clinical therapy. Furthermore, under the pressure of antibiotics used ubiquitously over the last 80 years, functional mutations and new resistances are continuously increasing. Therefore, new drugs and new approaches to the infections produced by multidrug-resistant Gram-negative bacteria are categorically necessary and expected by the scientific community. This review describes the most deleterious known extended-spectrum β- lactamases and the molecules now available for targeting bacterial infections. The active-site chemical and geometric properties that are potentially exploitable for the design of both broad-spectrum and selective compounds are described.