This article is about the chemical compound. For the related antibiotics, see
β-Lactam antibiotic.
A beta-lactam (β-lactam) ring is a four-membered
lactam.[1] 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 as manifested in many
β-lactam antibiotics.[2] Up to 1970, most β-lactam research was concerned with the
penicillin and
cephalosporin groups, but since then, a wide variety of structures have been described.[3][4]
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.[5] These enzymes vary widely in their chemical structure and catalytic efficiencies.[6] 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 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 (PBP), which have as function to cross-link the peptidoglycan part of the cell wall of the bacteria.[7]
Many methods have been developed for the synthesis of β-lactams.[10][11][12]
The Breckpot β-lactam synthesis[13] produces substituted β-lactams by the cyclization of beta amino acid esters by use of a
Grignard reagent.[14]Mukaiyama's reagent is also used in modified Breckpot synthesis.[13]
Reactions
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 (as the
apex) and its three adjacent atoms. h corresponds to the strength of the β-lactam bond with lower numbers (more planar; more like ideal amides) being stronger and less reactive.[15] Monobactams have h values between 0.05 and 0.10
angstroms (Å). 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.[16]
^Bogdanov B, Zdravkovski Z, Hristovski K.
"Breckpot Synthesis". Institute of Chemistry Skopje. Archived from
the original on 2015-11-06. Retrieved 2014-12-30.
^Nangia A, Biradha K, Desiraju GR (1996). "Correlation of biological activity in β-lactam antibiotics with Woodward and Cohen structural parameters: A Cambridge database study". J. Chem. Soc. Perkin Trans. 2 (5): 943–53.
doi:
10.1039/p29960000943.