Cell wall synthesis inhibitors

Giuseppe A BottaDileep K. Rohra

POD Block, Semester 32014-15

Learning Objectives• Classify the cell wall synthesis inhibitors.• Discuss the structure-activity relationship of b lactam

antibiotics.• Revisit the physiology of cell wall synthesis and

explain the mechanism of action of b lactam antibiotics and vancomycin.

• Describe the mechanisms of drug resistance against b lactam antibiotics.

• Discuss the role of b lactamase inhibitors in combination with b lactam antibiotics.

• Describe the clinical uses and adverse effects of b lactam antibiotics and vancomycin.

Classification of Antibiotics• Cell wall synthesis inhibitors:• b-lactam drugs (Penicillins, Cephalosporins,

Carbapenems, Monobactams), Vancomycin• Protein synthesis inhibitors:

• Aminoglycosides, Chloramphenicol, Tetracyclines, Macrolides, Clindamycin, Linezolid

• Nucleic acid synthesis inhibitors:• Fluoroquinolones

• Antimetabolites:• Sulfonamides, Trimethoprim

Cell wall synthesis inhibitors: Classification

β-Lactam Antibiotics

• Penicillins• Cephalosporins • Carbapenems• Monobactams

C NH CH CH C

O

O C N CH

CH3

CH3COOH

S

Penicillin: Structure

Thiozolidineb-lactam

Cell Wall synthesis• Cell walls of bacteria are essential for their

normal growth & development.• Peptidoglycan is a heteropolymeric

component of the cell wall that provides rigid mechanical stability by virtue of its highly cross-linked latticework structure.

• The peptidoglycan is composed of glycan chains, which are linear strands of two alternating amino sugars (N-acetylglucosamine and N-acetylmuramic acid) that are cross-linked by peptide chains. (NAG-NAM).

Bacterial cell wall synthesis

b lactams: Mechanism of action• It is this last step in peptidoglycan

synthesis that is inhibited by the b lactam antibiotics.

• Beta lactams bind at the active site of the transpeptidase enzyme (PBPs) that cross-link the peptidoglycan strands.

• Beta lactams irreversibly inhibit the enzyme transpeptidase by reacting with a serine residue.

b lactams: Mechanism of action

• Eventually, the growth of the bacterial cell wall is inhibited.

• In the presence of b lactams, autolysins are also released causing the lysis of the bacteria.

Inhibitory effects of b lactams on bacterial cell

wall

Mechanisms of bacterial resistance to penicillins

Resistance to penicillins & other b lactams is due to one of four general mechanisms:• Inactivation of the antibiotic by b

lactamase• Modification of target PBPs• Impaired penetration of drug to target

PBPs

C NH CH CH C

O

O C N CH

CH3

CH3COOH

S

Site of penicillinase action

Penicillin: Structure

Thiozolidineb-lactam

• Natural penicillins:– Benzylpenicillin; Gm +ves, anaerobes &

selected Gm –ves• Penicillinase resistant penicillins:

– Flucloxacillin, Cloxacillin; penicillin-resistant staphylococci. Also active against streptococci

• Aminopenicillins (extended-spectrum):– Amoxycillin, Ampicillin; as for penicillin G

+ Gram –ve cocci, & Enterobacteriaceae.

Penicillins: Classification

• Carboxypenicillins:– Carbenicillin, ticarcillin; as for

aminopenicillins + Gm –ve rods resistant to ampicillin, including P. aeruginosa.

• Ureidopenicillins:– Piperacillin; similar to carboxypenicillins

Penicillins: Classification

Mechanisms of bacterial resistance to penicillins

Resistance to penicillins & other b lactams is due to one of three general mechanisms:• Inactivation of the antibiotic by b

lactamase• Modification of target PBPs• Impaired penetration of drug to target

PBPs• The presence of an efflux pump

β-Lactamase Inhibitors

• Clavulanic acid, Sulbactam, Tazobactam

• Weak, unimportant antibacterial activity

• Powerful irreversible inhibitor of b-lactamases - suicide substrate

β-lactam/Inhibitor combinations

• Ampicillin + Sulbactam = Unasyn• Amoxicillin + Clavulanic acic =

Augmentin• Piperacillin + Tazobactam = Zosyn

Penicillins: Clinical uses

• Bacterial meningitis:– Caused by N meningitidis, S pneumoniae;

Benzylpenicillin• Bone & joint infections:

– E.g with Staph aureus; Flucloxacillin• Skin & soft tissue infections:

– E.g with S pyogenes or Staph aureus; Flucloxacillin• Pharyngitis:

– S pyogenes; phenoxymethylpenicillin

Penicillins: Clinical uses• Otitis media:

– E.g. with S pyogenes or H influenzae; Amoxicillin

• Bronchitis:– Amoxicillin

• UTIs:– Amoxicillin

• Infections with P aeruginosa:– Ticarcillin, Pipercillin

Penicillins: Adverse effects• Hypersensitivity Reactions:

– Most common adverse effects noted with the penicillins.

– Manifestations of allergy to penicillins include maculopapular rash, urticarial rash, fever, bronchospasm, vasculitis, serum sickness, exfoliative dermatitis, Stevens-Johnson syndrome, & anaphylaxis

– The overall incidence of such reactions to the penicillins varies from 0.7% to 10% in different studies

• Rarely, bone marrow depression, granulocytopenia, & hepatitis

Cephalosporins: ClassificationGeneration Example Spectrum

1st Cephalexin, Cefadroxil

Strep. Staph. aureus

2nd Cefaclor, Cefuroxime

E. coli, Klebsiella, Proteus, H. influenzae. Not as effective against G +ve as 1st generation

3rd Cefotaxime, Ceftriaxone, Cefixime

Enterobacteriaceae, Psudomonas, Serratia, N. gonorrhoeae, Staph. & Strep.

4th Cefepime, Comparable to 3rd generation but more resistant to some b-lactamases & greater activity against Gm +ve

Carbapenems

• Imipenem• Meropenem

Imipenem• Imipenem is always co-

administered with Cilastin; an inhibitor of renal dehydropeptidase I - enzyme responsible for hydrolysis of imipenem. Does increase the duration of action of Imipenem.

• Active against most clinically important bacteria including anaerobes.

• Not destroyed by most b lactamases

• Administere only IV• Adverse effects (Relatively

infrequent):– Phlebitis or pain at site of injection– Nausea, Vomiting– Fits (usually with pre-existing CNS

disease)

Imipenem

Monobactams: Aztreonam• Primarily active against aerobic Gram-

negative organisms • Used in severe sepsis, often hospital

acquired, especially infections of the respiratory, urinary, biliary, gastrointestinal & female genital tracts.

• Has a narrow spectrum of activity & cannot be used alone unless the organism´s sensitivity to aztreonam is known.

• Adverse effects include Rashes

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But in 2008…,

Mechanisms of bacterial resistance to penicillins

Resistance to penicillins & other b lactams is due to one of three general mechanisms:• Inactivation of the antibiotic by b

lactamase• Modification of target PBPs• Impaired penetration of drug to target

PBPs

• So what?

Vancomycin

• Vancomycin inhibits bacterial cell wall synthesis by inhibiting peptidoglycan polymerization at a step earlier than that inhibited by the b lactams.

• It is effective mainly against MRSA.

• Vancomycin is not absorbed from the gut, & is usually given as an intravenous infusion.

Vancomycin: Adverse effects

• Hearing loss• Venous thrombosis at infusion

site• “Red man” syndrome due to

cytokine/histamine release following rapid intravenous administration

• Hypersensitivity: rashes etc.• Nephrotoxicity