Antibiotic Agents Targeting Bacterial Cell Wall Synthesis (Gartenberg) -5/3/16

Question 1

Pathogenic Gram (+) Examples (6):

Pathogenic Gram (-) Examples (11):

Answer 1

Pathogenic Gram (+) Examples:

• Bacillus
• Listeria
• Staphylococcus
• Streptococcus
• Enterococcus
• Clostridium

Pathogenic Gram (-) Examples:

1) Respiratory
- Hemophilus influenza
- Klebsiella pneumoniae
- Legionella pneumonphila
- Pseudomonas aeruginosa

2) GI
- Helicobacter pylori
- Salmonella penteritidis
- Salmonella typhi

3) UTI
- E. coli
- Enterobacter
- Serratia

Question 2

What are broad spectrum drugs?

Answer 2

Drugs that work against both classes of bacteria

Question 3

The outer membrane of Gram (-) bacteria is relatively impervious. How do drugs get through?

Answer 3

Transmembrane pores - typically favor small hydrophilic drugs

Gram (-) drugs are resistant against big drugs like vancomycin and daptomycin.

Question 4

Transglycosylase enzyme?

Transpeptidase enzymes?

Answer 4

Transglycosylase enzymes = join sugars that make polysaccharide chains (glue)

Transpeptidase enzymes = join sugar-linked peptides to x-linked polysaccharide chains (make cross links - penicillin target)

Question 5

4 primary beta-lactam antibiotic families?

Answer 5

1. Penicillin (+5 C ring)
2. Monobactam
3. Cephalosporin (+6 C ring)
4. Carbapenem (+6 C ring)

Question 6

Mechanism of beta-lactam action?

Answer 6

Penicillin prevents peptidoglycan cross-linking –> dead enzyme

Bactericidal during peptidoglycan production.
- Only kills growing cells!

Question 7

What are beta-lactamases?

Mechanism of beta-lactamase action?

Answer 7

Enzymes (aka penicillinases) produced by bacteria that provide resistance to beta-lactam antibiotics

Gram (-) bacterial response to beta-lactam antibiotics:
- Serine beta-lactamases = similar to transpeptidases - however, they use H2O to hydrolyze serine-lactam linkage

Hydrolyzed beta-lactam has NO THERAPEUTIC VALUE

Question 8

Function of beta-lactamase inhibitors?

Three examples of beta-lactamase inhibitors?

Answer 8

• NO antibacterial activity
• Combined w/ beta-lactam antibiotics to extend their 1/2 life
• Inhibitors bind beta-lactamases covalently and inactivate irreversibly (like how beta lactams bind transpeptidases)

3 examples:

• Clavulanic acid (most active against plasmid encoded beta-lactamases in staph, h. influenza, n. gonorrhoeae, salmonella, shigella, E. coli, K. pneumonia); (least active against chromosomally-encoded beta-lactamases in enterobacter, citrobacter, serrate, pseudomonas)
• Sulbactam
• Tazobactam

Question 9

Avibactam?

Answer 9

Broader spectrum beta-lactamase inhibitor

Serine beta-lactamases come in three classes: A, C, and D

Traditional beta-lactamase inhibitors work primarily on class A enzymes

Avibactam = broader spectrum beta-lactamase inhibitor (new in 2015) that works on class A and C, and sometimes D enzymes

NOTE: inhibitor does NOT contain beta-lactam core

Question 10

What makes different classes of penicillin distinct?

Answer 10

All have common core but R group makes each distinct

Common penicillins
- Penicillin G (acid labile, beta-lactamase susceptible)

Anti-staphylococcal penicillins
- Oxacillin (no Cl) - acid stable, beta-lactamase resistant

Extended-spectrum penicillins
- Amoxicillin (acid stable, greater activity against gram- b/c of their ability to penetrate outer membrane; inactivated by lactamases; available in combination with beta-lactamase inhibitors e.g. amoxicillin + clavulanate = augmentin)

Question 11

Cephalosporins?

Answer 11

Broader spectrum due to increased resistance to beta-lactamases

1st generation: cefazolin

• Broad spectrum but better for gram +
• Restricted to surgical prophylaxis
• Does not penetrate CNS

2nd generation: cefamandole

• Extend the coverage of gram - bacteria over 1st generation
• No allergic cross-reactivity w/ penicillin

3rd generation: ceftazidime

• Extend gram - activity at expense of gram + activity
• Some cross blood-brain barrier
• Ceftazidime + beta-lactamase inhibitor (avibactam) = Avycaz

4th generation: cefepime

• More resistant to chromosomal beta-lactamases
• True broad spectrum drugs
• Penetrates CNS

5th generation: ceftolozane

6th generation: cefaroline
- Used against MRSA

Question 12

Monobactams?

Answer 12

Monocyclic drugs w/ only a single lactam ring

ONLY GOOD AGAINST GRAM NEGATIVE BACTERIA

Transpeptidases in gram+ don’t recognize the drug

Question 13

Carbapenems?

Answer 13

Broad spectrum antibiotics w/ good activity against many gram negative rods, gram + bacteria, and anaerobes - used for mixed infections

Cross-sensitivity in patients w/ penicillin allergies

Question 14

Non beta-lactam drugs?

Answer 14

Vancomycin:

• Active against gram + bacteria (esp. staph)
• Bactericidal for actively growing cells
• BINDS CELL WALL (substrate) RATHER THAN ENZYMES USED TO MAKE IT
• so bulky / prevents two reactions needed to make peptidoglycan layer - binds D-ala-D-ala

Daptomycin:

• Against Gram +
• Bacterial cell membrane pore former
• Allows K+ loss without cell rupture (kills bugs by leaking potassium contents) - kill bugs without releasing toxins

Polymyxins:

• bind OUTER MEMBRANE of gram (-) bacteria ultimately leading to permeability of both inner and outer membranes
• recognizes lipopolysaccharides… doesn’t make pores… actually splits outer membrane to make it accessible to other drugs

Question 15

Drugs that target PRECURSORS that make PG layer (3):

Answer 15

Fosftomycin (inhibits conversion of NAG-UDP to NAM-UDP)

Bacitracin (active against gram positive - inactivates lipid phosphatase that dephosphorylates lipid carrier of PG subunits) –> without it, can’t build chain

D-cycloserine (used in combo with other antibiotics to treat TB) - inhibits joining of D-ala to another D-ala