Antibiotics-

Cell Wall Inhibitors

Pharmacology L3
PHCL-L3-AntiMicro-lecture2

1
 Learning Objectives
 Describe essential steps in the synthesis and
constitution of cell wall
 Explain the mechanism of action of β-lactam
antibiotics and other inhibitors of cellwall synthesis
 Classify β-lactam antibiotics and other inhibitors of
cellwall synthesis
 Describe the structural relationship of the β-lactam
molecule with antimicrobial activity
 Understand the mechanism of resistance to
penicillin and involvement of β-lactamase
 Understand the principle of combination of
inhibitors of β-lactamase with penicillins
2
3
Inhibitors of cell wall synthesis
 Classification
► Beta-lactam Antibiotics
• Penicillins (Derived from Penicillium)
• Cephalosporins (from Cephalosporium)
• Carbapenems (Synthetic)
• Monobactams
• New and experimental agents
► Others..
• Inhibitors of synthesis of Monomer
– Fosfomycin, bacitracin
• Inhibitors of polymerisation
– vancomycin

4
 Cell wall synthesis inhibitors

III III III

Penicillins Cephalosporins Other beta-lactams Other cell wall
synthesis inhibitors
Penicillin G Aztreonam
Penicillin V Imipenem/Cilastatin Vancomycin II
Meropenem Fosfomycin I
P Nafcillin L  antistaph Bacitracin
OOxacillin
Clavulanic Acid
II
Ampicillin
Amoxicillin

Ticarcillin
Piperacillinantipseudo

First generation Second Third generation Fourth generation

Cell wall synth. generation
Cephalexin O Ceftriaxone L Cefepime
I = 1st stage Cefazolin Cefoxitin Ceftazidime
II = 2nd stage Cefadroxil
O
Cefaclor O Cefoperazone L
Cefotetan Cefpodoxime
III = 3rd stage Cefuroxime O,P proxetil O
L = liver elimin. Cefixime
O = oral
P = Parenteral
 Target: the Bacterial Cell Wall
 Three steps in cell wall synthesis can be targets for
antibacterial drugs:
► Synthesis of murein monomers
• Synthesized from amino acids and sugars
► Polymerization
• Monomer ferried by lipid carrier molecule, bactoprenol to outer
surface of cytoplasmic membrane
• Bactoprenol phosphate transports NAM and NAG across the
cell membrane in the synthesis of peptidoglycan. Bacitracin inhibits
this process

► Crosslinking
• Enzymes called transpeptidases also known as penicillin-binding
proteins, crosslink murein chains
• transpeptidases are inhibited by b lactams
• They irreversibly binds to and inhibits the activity of the
transpeptidase enzyme by forming a highly stable penicilloyl-enzyme
intermediate.
• Because of the interaction between penicillin and transpeptidase,
this enzyme is also known as "penicillin-binding protein."
6
7
8
9
10
11
Inhibitors of monomer synthesis
 Fosfomycin/Fosmidomycin
► Gram neg UTI
 Cycloserine
► Second line M. tuberculosis
 Bacitracin
► Topical infections

12
 Inhibitors of polymerization
 Vancomycin
► Binds tightly to D-Ala- D-
Ala terminal of murein
monomer
► Prevents linking of
monomers
 Vanco Resistance:
► Bacteria
coded to produce
D- Ala-D-lactate (not
bound by Vanco)
13
 Inhibitors of crosslinking
 Beta-lactam antibiotics
► Permanently bind bacterial enzymes involved
in crosslinking peptides
► Inhibition in this step of cell wall synthesis
results in autolysis and cell death
• Beta-lactam antibiotics are bactericidal for actively
dividing bacteria

14
Inhibition of Cell Wall Synthesis

Penicillin-binding proteins (PBPs(

Transpeptidases, Carboxypeptidases, Transglycosylases

β-Lactam antibiotics: generally are bactericidal agents

-Lactam Structure

16
17
Summary of antimicrobial agents affecting cell wall
synthesis
Agents affecting the
cell wall -lactamase
inhibitors
Clavulanic acid
-lactam antibiotics Other antibiotics Sulbactam
Bacitracin Tazobactam
Vancomycin
Daptomycin

Penicillins Cephalosporins Carbapenems Monobactams

Amoxicillin Ertapenem
Imipenem/cilastatin* Aztreonam
Ampicillin Meropenem
Dicloxacillin
Indanyl carbenicillin
Methicillin 1st generation 2nd generation 3rd generation 4th generation
Nafcillin Cefadroxil
Oxacillin Cefaclor Cefdinir Cefepime
Cefazolin Cefprozil Cefixime
Penicillin G Cephalexin Cefuroxime
Penicillin V Cefotaxime
Cefoxitin Ceftazidime
Piperacillin Ceftibuten
Ticarcillin Ceftizoxime
Ceftriaxone

(according to Lippincott´s Pharmacology, 2009)

Repertoire of β-lactam
2014

20
Beta-lactam Antibiotics

Anti-staphylcoccal penicillins

Biliary secretion

Antipseudomnal penicillins

Ampicillin or
Amoxicillin rash
Antibiotics with beta-
lactam structure

Monobactam: effective against Gram

negative bacteria only
Carbapenem (imipenem): broadest
spectrum beta-lactams, resistant to
beta-lactamases
Imipenem, Meropenem

Clavulinic acid: “suicide compound

”, beta-lactamase inhibitor
 General Pharmacology of
-Lactams

 PK
► Absorption
• Many penicillins degraded by gastric acid
• Oral -lactams are variably absorbed;
• Food delays rate and extent of absorption
• Pen V absorbed better than oral Pen G
• Amoxicillin absorbed better than ampicillin
► Distribution

• Widely distributed into tissues and fluids

• Parenteral penicillins only get into CSF in the
presence of inflamed meninges; 24
 -Lactams
Pharmacology
• Elimination
► Most eliminated primarily by the kidney,
► excreted by tubular secretion (Organic Acid Secretory
System)
► Block by Probenecid
► dosage adjustment of these agents is required in the
presence of renal insufficiency
► Nafcillin, oxacillin,are eliminated primarily by the liver;
► piperacillin also undergoes some hepatic elimination
► ALL -lactams have short elimination half-lives (< 2º),

25
 Genearal Pharmacology of
-Lactams……
 PD
• Concentration-independent bacterial killing;
• Time above MIC correlates with efficacy

26
 Genearal Pharmacology of
-Lactams……
 Resistance:
► Mechanisms of resistance:
1. Production of -LACTAMASE

2. Alteration in penicillin binding proteins (PBP)

3. Decreased entry of -lactams (cell membrane and cell

wall structure; porin mechanism)

4. Increased efflux of -lactams

27