7 - Monobactams

Abstract

This chapter provides an overview of the isolation and synthesis of monobactams and their microbiological activity. The discovery of the monobactams has caused a significant change in the definition of the structural parameters necessary for antimicrobial activity of β-lactams. Electron withdrawal by the sulfur atom at the 4-position of the azetidinone ring contributes to the activation of the β-lactam in both penicillin and cephalosporin. In contrast, the monobactams are monocyclic β-lactam antibiotics where activation is achieved solely by electronic effects. X-ray crystallographic data indicate there is no steric activation as the azetidinone ring is planar with the sulfonate residue lying within the plane. Electron withdrawal by the sulfonate group is responsible for the activation of the β-lactam in the monobactams. An essential structural feature of β-lactam antibiotics is the carboxylate anion proximate to the β-lactam ring. In the monobactams, the relatively long S—N and S—O bond lengths place the sulfonate oxygen atoms, with respect to the ring, in a position coincident with the carboxylate oxygen atoms in penicillin. The sulfonate group plays a multiple role in balancing activation and stability of the β-lactam ring while positioning the anionic charge for recognition by the enzyme.