Cell Wall Synthesis Inhibitors Part 2

Cell wall synthesis inhibitors work by

Preventing the formation of a functional peptidoglycan cell wall.

Primary target of cell wall inhibitors

Peptidoglycan synthesis.

Three major stages of bacterial cell wall synthesis

First stage (cytoplasm), second stage (cell membrane), and third stage (outside membrane).

First stage of cell wall synthesis occurs in

The cytoplasm.

Second stage of cell wall synthesis occurs at

The cell membrane.

Third stage of cell wall synthesis occurs

Outside the cell membrane during cross-linking.

Penicillins - Mechanism of Action

Bind to penicillin-binding proteins and inhibit transpeptidation.

Cephalosporins - Mechanism of Action

Bind to penicillin-binding proteins and inhibit transpeptidation.

Monobactams - Mechanism of Action

Bind to penicillin-binding proteins and inhibit transpeptidation.

Carbapenems - Mechanism of Action

Bind to penicillin-binding proteins and inhibit transpeptidation.

Penicillin-binding proteins (PBPs) are

Enzymes involved in bacterial cell wall synthesis.

Function of PBPs

Catalyze cross-linking of peptidoglycan chains.

What is transpeptidation?

Cross-linking of peptidoglycan strands in the bacterial cell wall.

Effect of inhibiting transpeptidation

Weak, unstable bacterial cell wall.

Final result of beta-lactam action

Bacterial lysis and death.

Why beta-lactams are bactericidal

They destroy cell wall integrity.

Beta-lactams work best against

Actively dividing bacteria.

Why beta-lactams require bacterial growth

New cell wall synthesis must be occurring.

Penicillins primarily bind

PBPs.

Cephalosporins primarily bind

PBPs.

Aztreonam primarily binds

PBPs of Gram-negative aerobic bacteria.

Carbapenems bind

Multiple PBPs.

Why carbapenems are more bactericidal than many beta-lactams

They bind more PBPs and produce postantibiotic effects.

Carbapenems especially affect

PBP-1 and PBP-2.

Postantibiotic effect (PAE)

Persistent suppression of bacterial growth after drug concentrations fall.

Carbapenems produce PAE against

Gram-negative bacteria.

Advantage of carbapenems in Gram-negative sepsis

Less endotoxin release due to rapid bacterial killing.

Cephalosporins usually bind which PBPs?

PBP-2 and PBP-3.

Monobactam prototype

Aztreonam.

Aztreonam disrupts

Cell wall synthesis in Gram-negative aerobic bacteria.

Aztreonam is stable against

Most beta-lactamases.

Fosfomycin - Mechanism of Action

Irreversibly inhibits phosphoenolpyruvate transferase.

Fosfomycin is a structural analogue of

Phosphoenolpyruvate (PEP).

Target enzyme of fosfomycin

Phosphoenolpyruvate transferase.

Role of phosphoenolpyruvate transferase

Catalyzes the first step of peptidoglycan synthesis.

Stage of cell wall synthesis inhibited by fosfomycin

First stage.

Result of fosfomycin action

Failure to form peptidoglycan precursors.

Fosfomycin binding to its target

Irreversible.

Fosfomycin is

Bactericidal at therapeutic concentrations.

Bacitracin - Mechanism of Action

Inhibits the second stage of bacterial cell wall synthesis.

Stage of cell wall synthesis inhibited by bacitracin

Second stage.

How bacitracin inhibits cell wall synthesis

Blocks phosphorylase reactions involved in peptidoglycan synthesis.

Additional effect of bacitracin

Interferes with cell membrane function.

Another effect of bacitracin

Inhibits protein synthesis.

Bactericidal activity of bacitracin requires

Divalent cations such as zinc.

Most active component of bacitracin preparations

Bacitracin A.

Vancomycin - Mechanism of Action

Inhibits the second stage of bacterial cell wall synthesis.

Stage of cell wall synthesis inhibited by vancomycin

Second stage.

How vancomycin works

Blocks transfer of glycopeptide chains to the acceptor site.

Effect of vancomycin action

Prevents peptidoglycan polymer formation.

Vancomycin produces what type of effect?

Rapid bactericidal effect.

Vancomycin is especially effective against

Dividing bacteria.

Penicillins, cephalosporins, monobactams, and carbapenems inhibit

Third stage of cell wall synthesis.

Bacitracin and vancomycin inhibit

Second stage of cell wall synthesis.

Fosfomycin inhibits

First stage of cell wall synthesis.

Drug inhibiting the earliest stage of cell wall synthesis

Fosfomycin.

Drug inhibiting phosphorylase reactions

Bacitracin.

Drug inhibiting glycopeptide transfer

Vancomycin.

Drug binding PBPs

Penicillins, Cephalosporins, Monobactams, and Carbapenems.

Drug affecting the greatest number of PBPs

Carbapenems.

Drug stable against most beta-lactamases

Aztreonam.

Most important mechanism of penicillins

PBP inhibition.

Most important mechanism of cephalosporins

PBP inhibition.

Most important mechanism of carbapenems

PBP inhibition with broader binding.

Most important mechanism of fosfomycin

Inhibition of phosphoenolpyruvate transferase.

Most important mechanism of bacitracin

Blockade of phosphorylase reactions.

Most important mechanism of vancomycin

Blockade of glycopeptide transfer.

High-yield MOA association

Fosfomycin = First stage inhibitor.

High-yield MOA association

Bacitracin = Second stage inhibitor.

High-yield MOA association

Vancomycin = Second stage inhibitor.

High-yield MOA association

Penicillins = Third stage inhibitor.

High-yield MOA association

Cephalosporins = Third stage inhibitor.

High-yield MOA association

Aztreonam = Third stage inhibitor.

High-yield MOA association

Carbapenems = Third stage inhibitor.

Mnemonic for stages

Fosfo First, Baci & Vanco Second, Beta-lactams Third.

Most frequently tested MOA

β-lactams inhibit transpeptidation.

Most frequently tested MOA

Fosfomycin inhibits phosphoenolpyruvate transferase.

Most frequently tested MOA

Bacitracin inhibits phosphorylase reactions.

Most frequently tested MOA

Vancomycin blocks glycopeptide transfer.

Most frequently tested MOA

Carbapenems bind multiple PBPs.