Cell Wall Inhibitors (Micro L.13 & L.14)

What are the two major types of cell wall synthesis inhibitors?

Beta-lactam drugs and non-beta-lactam drugs.

What is the overall goal of cell wall synthesis inhibitors?

Prevent bacteria from building a functional peptidoglycan cell wall.

What are the four classes of beta-lactam drugs?

Penicillins, cephalosporins, carbapenems and monobactams.

What are the non-beta-lactam cell wall inhibitors?

Vancomycin, bacitracin, cycloserine and potentially teixobactin.

What is transpeptidation?

The formation of cross-links in peptidoglycan during bacterial cell wall synthesis.

What are PBPs?

Penicillin-binding proteins; bacterial proteins involved in peptidoglycan biosynthesis.

What is the result of preventing proper cell wall synthesis?

The bacterium cannot form a complete functional cell wall and may undergo osmotic lysis.

Why are penicillins most effective against growing bacteria?

Growing bacteria are actively synthesizing new peptidoglycan.

Penicillins: mode of action

Their beta-lactam ring blocks the enzyme responsible for transpeptidation, preventing peptidoglycan cross-linking and leading to osmotic lysis.

Penicillins: other actions

Bind PBPs and may activate autolysins, murein hydrolases and holins.

Penicillins: main resistance mechanisms

Beta-lactamase destroys the beta-lactam ring; altered or upregulated transpeptidases can reduce the drug's effectiveness.

Penicillins: how beta-lactamase resistance can be overcome

Combine a penicillin with a beta-lactamase inhibitor, such as clavulanic acid or tazobactam, to protect the antibiotic from enzymatic destruction.

Naturally occurring penicillin examples

Penicillin G and Penicillin V; both are narrow-spectrum.

Broad-spectrum semisynthetic penicillins

Ampicillin, amoxicillin, carbenicillin, ticarcillin, piperacillin and mezlocillin.

Carbenicillin and ticarcillin: special feature

An extra carboxy group helps penetration into Pseudomonas and Bacteroides; they have moderate beta-lactamase resistance.

Piperacillin: special feature

A urea-like group protects its beta-lactam ring; it is used intravenously against many Gram-negative bacteria.

Penicillins with beta-lactamase resistance

Methicillin, oxacillin, cloxacillin and dicloxacillin.

Clavulanate and tazobactam

These are beta-lactamase inhibitors, sometimes called suicide drugs.

Augmentin

Amoxicillin plus clavulanate.

Timentin

Ticarcillin plus clavulanate.

Zosyn

Piperacillin plus tazobactam.

Cephalosporins: mode of action

Beta-lactam drugs that inhibit cell wall synthesis by interfering with PBPs and peptidoglycan cross-linking.

Cephalosporins: resistance

As beta-lactams, they can be affected by beta-lactamase and altered drug targets.

Why are cephalosporins divided into generations?

Each successive generation generally has a broader spectrum of activity and better effectiveness against Gram-negative bacteria.

Carbapenems: mode of action

Beta-lactam inhibitors of bacterial cell wall synthesis.

Carbapenems: resistance advantage

Highly resistant to beta-lactamases, although resistance can still emerge.

Carbapenem example

Imipenem.

Imipenem: spectrum

Broad-spectrum; highly effective against Gram-positive bacteria, Gram-negative bacteria and anaerobes.

Imipenem: clinical significance

Given intravenously in hospitals and as a last-resort drug.

Monobactams: mode of action

Beta-lactam drugs that bind and inactivate PBPs, inhibiting cell wall synthesis; bactericidal.

Monobactam example

Aztreonam.

Aztreonam: spectrum

Narrow-spectrum; effective only against Gram-negative bacteria,

Aztreonam: resistance feature

Contains a penicillinase-resistant beta-lactam ring.

Aztreonam: administration

Cannot be given orally. Too concentrated.

Vancomycin: class

Non-beta-lactam glycopeptide antibiotic.

Vancomycin: mode of action

Binds the emerging cell wall precursor by hydrogen bonding to the D-Ala-D-Ala end of its pentapeptide, preventing transpeptidation through steric hindrance.

Vancomycin: resistance

Bacteria alter the terminal D-Ala-D-Ala target, reducing vancomycin binding.

Vancomycin: resistance strategy

Changing the cell wall precursor's terminal target from D-Ala-D-Ala to an altered terminus reduces drug binding.

Vancomycin: spectrum

Narrow-spectrum and bactericidal against Gram-positive bacteria.

Groups that are susceptible to Vancomycin

Staphylococcus, Streptococcus, Clostridium, Bacillus and Enterococcus.

Bacitracin: mode of action

Prevents recycling of the bactoprenol shuttle needed to transport cell wall building blocks.

Bacitracin: spectrum

Broad-spectrum against Gram-positive and Gram-negative bacteria.

Bacitracin: clinical limitation

Toxic when used systemically and poorly absorbed orally, so it is used topically.

Bacitracin: example

An antibiotic in Neosporin's "triple" antibiotic.

What are the three antibiotics in Neosporin?

Bacitracin, neomycin and polymyxin.

Cycloserine: mode of action

Inhibits cell wall biosynthesis; it is a cyclic analog of D-alanine.

Cycloserine: example

Seromycin.

Cycloserine: clinical use

An oral second-line drug against Mycobacterium tuberculosis.

Cycloserine: limitation

Can penetrate the central nervous system and cause neurological side effects.

What enzyme destroys beta-lactam antibiotics?

Beta-lactamase; it destroys the beta-lactam ring.

How can bacteria resist penicillins by changing the drug target?

They can produce or upregulate altered transpeptidase enzymes, reducing the effectiveness of the drug.

How do clavulanate and tazobactam help beta-lactam antibiotics?

They inhibit beta-lactamase and help protect the paired antibiotic from destruction.

How do bacteria resist vancomycin?

They alter the terminal D-alanine-D-alanine target on the cell wall precursor, reducing drug binding.

Which cell wall inhibitor blocks bactoprenol recycling?

Bacitracin.

Which cell wall inhibitor binds D-Ala-D-Ala?

Vancomycin.

Which cell wall inhibitor is a cyclic analog of D-alanine?

Cycloserine.