Beta-lactam Antibiotics

Overview
  • The Beta-lactam Antibiotics are the largest class of bacterial cell wall synthesis inhibitors. This class of antibacterials share a common mechanism of action and a common structural motif known as the "Beta-lactam Ring" which gives the class its namesake. Various beta-lactam subclasses have been defined based on how the basic beta-lactam ring has been chemically modified.
Basic Structure
  • Above is pictured the basic beta-lactam ring. A variety of chemical structures replace the "R" group and determine the specific features of individual beta-lactam drugs.
Mechanism of Action
  • The beta-lactam antibiotics inhibit bacterial cell wall synthesis by targeting bacterial transpeptidase, the enzyme responsible for cross-linking of peptidoglycan subunits within the bacterial cell wall. Without the structural support of cross-linked peptidoglycan, bacteria are sensitive to a variety of environmental stresses that result in lysis of the bacteria; consequently, beta-lactam antibiotics are bactericidal.
Resistance
  • Overview
    • Several basic mechanisms have evolved among bacteria which can render microorganisms impervious to the actions of beta-lactam antibiotics. Depending on their individual structure, certain beta-lactams may or may not be prone to these resistance mechanisms.
  • Beta-lactamases
    • Certain bacteria have developed enzymes, known as "beta-lactamases", which can cleave the beta-lactam ring and thus inactivate the drug. Different beta-lactams are more or less susceptible to these beta-lactamases and relatively resistant beta-lactams are used during therapy if beta-lactamases are of concern. Additionally, a class of drugs known as beta-lactamase inhibitors (See links below) can be given in conjunction with the beta-lactam antibiotic. Beta-lactamase inhibitors inhibit bacterial beta-lactamase, thus preventing inactivation of the beta-lactam and re-establishing its bactericidal activity.
  • Altered Transpeptidase
    • Recall that beta-lactams function by binding and inactivating the enzymatic activity of bacterial transpeptidase which is sometimes termed the "Penicillin Binding Protein (PBP)". The transpeptidase of bacteria can mutate in such a way that it no longer binds certain beta-lactams, rendering the organisms impervious to the drug. Importantly, addition of beta-lactamase Inhibitors are not effective in the context of an altered PBP.
  • Altered Permeability
    • Recall from our discussion of the bacterial cell wall that the peptidoglycan layer of gram negative bacteria lies under the bacterial outer membrane. Beta-lactam antibiotics normally reach the peptidogycan layer of gram negative organisms by passing through pores within the bacterial outer membrane created by "Porin" molecules. Certain gram negative bacteria possess mutated porin molecules through which certain beta-lactams cannot pass, thus rendering these organisms impervious to the antibiotic. Additionally, certain gram negative bacteria have developed specialized enzymatic pumps which actively transport broad ranges of beta-lactams out of the periplasmic space.
Member Beta-lactam Classes