A beta-lactam ring is a four-membered lactam. A lactam is a cyclic amide, and beta-lactams are named so because the nitrogen atom is attached to the β-carbon atom relative to the carbonyl. The simplest β-lactam possible is 2-azetidinone. β-lactams are significant structural units of medicines.
Clinical significance
The β-lactam ring is part of the core structure of several antibiotic families, the principal ones being the penicillins, cephalosporins, carbapenems, and monobactams, which are, therefore, also called β-lactam antibiotics. Nearly all of these antibiotics work by inhibiting bacterial cell wall biosynthesis. This has a lethal effect on bacteria, although any given bacteria population will typically contain a subgroup that is resistant to β-lactam antibiotics. Bacterial resistance occurs as a result of the expression of one of many genes for the production of β-lactamases, a class of enzymes that break open the β-lactam ring. More than 1,800 different β-lactamase enzymes have been documented in various species of bacteria. These enzymes vary widely in their chemical structure and catalytic efficiencies. When bacterial populations have these resistant subgroups, treatment with β-lactam can result in the resistant strain becoming more prevalent and therefore more virulent. β-lactam derived antibiotics can be considered as one of the most important antibiotic classes but prone to clinical resistance. β-lactam exhibits its antibiotic properties by imitating the naturally occurring d-Ala-d-Ala substrate for the group of enzymes known as penicillin binding proteins, which have as function to cross-link the peptidoglycan part of the cell wall of the bacteria.
Many methods have been developed for the synthesis of β-lactams. Breckpot synthesis: The synthesis of substituted β-lactams from the cyclization of beta amino acid esters using the Grignard reagent. Due to ring strain, β-lactams are more readily hydrolyzed than linear amides or larger lactams. This strain is further increased by fusion to a second ring, as found in most β-lactam antibiotics. This trend is due to the amide character of the β-lactam being reduced by the aplanarity of the system. The nitrogen atom of an ideal amide is sp2-hybridized due to resonance, and sp2-hybridized atoms have trigonal planar bond geometry. As a pyramidal bond geometry is forced upon the nitrogen atom by the ring strain, the resonance of the amide bond is reduced, and the carbonyl becomes more ketone-like. Nobel laureateRobert Burns Woodward described a parameter h as a measure of the height of the trigonal pyramid defined by the nitrogen and its three adjacent atoms. h corresponds to the strength of the β-lactam bond with lower numbers being stronger and less reactive. Monobactams have h values between 0.05 and 0.10 angstroms. Cephems have h values in of 0.20-0.25 Å. Penams have values in the range 0.40-0.50 Å, while carbapenems and clavams have values of 0.50-0.60 Å, being the most reactive of the β-lactams toward hydrolysis.
Other applications
A new study has suggested that β-lactams can undergo ring-opening polymerization to form amide bonds, to become nylon-3 polymers. The backbones of these polymers are identical to peptides, which offer them biofunctionality. These nylon-3 polymers can either mimic host defense peptides or act as signals to stimulate 3T3 stem cell function. Antiproliferative agents that target tubulin with β-lactams in their structure have also been reported.
