Mechanism of action of Penicillin

Penicillin kills bacteria through binding of the beta-lactam ring to DD-transpeptidase,

inhibiting its cross-linking activity and preventing new cell wall formation. Without a cell
wall, a bacterial cell is vulnerable to outside water and molecular pressures, and quickly
dies.

Penicillin are bactericidal agents that exert their mechanism of action by inhibition of
bacterial cell wall synthesis and by inducing a bacterial autolytic effect.
Inhibition of Bacterial Cell Wall Synthesis
Penicillin exert their bactericidal activity primarily by inhibiting bacterial cell wall synthesis.
Though the exact mechanism of action is not fully elucidated, it appears that penicillin bind
to penicillin-binding proteins (PBPs), which are enzymes (transpeptidases,
carboxypeptidases, and endopeptidases) that play an important role in the formation and
maintenance of the cell wall structure. The cell wall is made up of peptidoglycan, or murein
sacculus, which is a polymeric component consisting of long polysaccharide chains of N-
acetylglucosamine and N-acetylmuramic acid cross-linked by shorter peptide chains. The
formation of peptidoglycan can be divided into three stages, including precursor formation in
the cytoplasm, linkage of precursor products into a long polymer, and finally cross-linking by
transpeptidation. It is the final transpeptidation process that is inhibited by penicillin by
acting as a structural analog of acyl-D-alanyl-D-alanine (the substrate of the enzyme) and
acylating the transpeptidase enzyme. The peptidoglycan structure, and therefore the cell wall
structure, is weakened, leading to cell death. Other mechanisms of cell death are also
possible. Also, there are differences in PBPs between gram-positive and gram-negative
bacteria and there are differences in affinity between penicillin compounds to various PBPs.
These differences can affect spectrum of activity.
Penicillin-Induced Bacterial Autolytic Effect
There are several PBPs that the penicillin simultaneously inactivates. Inhibition of certain
PBPs may be related to the activation of a bacterial autolytic process by inactivation of
endogenous inhibitors of these autolysins or murein hydrolases. These enzymes cleave parts
of the cell wall to make room for peptidoglycan synthesis for cell wall expansion. With
inhibition of cell wall synthesis, bacterial lysis can occur due to increased osmotic pressure.
This autolysis may be cell cycle dependent, that is, most likely to occur while the cell is
dividing. Certain “tolerant” species of staphylococci and streptococci have been isolated
which are autolysin-deficient. These organisms are inhibited, but not killed by penicillin