Antibacterial Antibiotics

Question 1

What counts as a “good” antibiotic

Answer 1

1. Product of metabolism or semi-synthetic analogue of a naturally-occurring substance
2. Antagonizes the growth or survival of one or more species of microorganisms
3. Effective in low concentrations
4. Selectively toxic to organism/tissue without causing significant toxic side effects
5. Stable enough to be isolated and stored
6. Metabolism and clearance rates are amenable to dosing regimens

Question 2

Beta-lactam antibiotics

Answer 2

Most common class of bacterial antibiotics
3 classes: penicillins (4-ring/5-ring systems), cephalosporins (4-ring/6-ring systems), monobactams
Selective inhibitors of bacterial cell wall biosynthesis

Question 3

Penicillin chemical reactivity

Answer 3

Unstable to strongly acidic or basic conditions (breaking open penicillin ring destroys antibacterial functionality)

Question 4

Beta-lactamase inhibitors

Answer 4

Mechanism-based inhibitors of beta-lactamase (enzyme that degrades penicillin)

Question 5

Cephalosporin chemical reactivity

Answer 5

More resistant to beta-lactamases than penicillins

Deacylation of structure results in drug inactivation

Question 6

Monobactams

Answer 6

Monocyclic class of beta-lactam antibiotics
Not heavily used

Question 7

Aminoglycosides

Answer 7

Broad spectrum antibiotics used to treat both GI and systemic infections
Example: streptomycin
General structure of glycosidically-linked amino-sugars
Bind 30S ribosomal subunit to prevent initiation of amino acid polymerization

Question 8

Aminoglycoside resistance

Answer 8

Though they aren’t metabolized, bacteria have enzymes to inactivate them, such as amino-acetyltransferases

Question 9

Aminoglycoside SAR

Answer 9

Ring 1: critical for broad-spectrum activity and primary target for inactivating enzymes
Ring 2: deoxystreptamine ring cannot be significantly changed without loss of activity
Ring 3: more tolerant to structural modifications

Question 10

Tetracyclines

Answer 10

Probably most important class of broad-spectrum antibiotics
Characteristic fused ring system
Stable chelation complexes with Ca+2, Mg+2, and Fe+2 (reason why dairy products can’t be consumed while taking them)

Question 11

Tetracycline mechanism of action

Answer 11

Bind the 30S ribosomal subunit and prevent “docking” of amino-acyl tRNAs to A site

Question 12

Tetracycline SAR

Answer 12

Analogs with fewer than 4 rings are inactive

Southern and eastern portions of system can’t be significantly modified without loss of activity

Question 13

Macrolide antibiotics

Answer 13

3 common characteristics: 
Large lactone ring (12-16 atoms)
Ketone group
Glycosidically linked sugar
Examples: erythromycin, azithromycin

Question 14

Macrolide antibiotic mechanism of action

Answer 14

Bind to bacterial 50S ribosomal subunit, preventing translocation step in protein synthesis (can’t switch from A site to P site)

Question 15

Polypeptide antibiotics

Answer 15

Some of the most powerful antibiotics
Renal toxicity and poor oral bioavailability
Significant structural diversity (most have a cyclic structure, D-amino acids, and other non-amino acid moieties)

Question 16

Polypeptide antibiotic mechanism of action

Answer 16

Bacitracin and vancomycin inhibit bacterial cell wall synthesis
Gramicidins and polymyxins interfere with cell membrane function

Question 17

Vancomycin

Answer 17

Inhibits cell wall synthesis by binding to the D-Ala-D-Ala terminus of the growing polypeptide “crosslink”
Typically considered the antibiotic last line of defense

Question 18

Chloramphenicol

Answer 18

First broad-spectrum antibiotic
Inhibits bacterial protein synthesis (mechanism still not totally understood)
Contains a para-nitro group (unusual in biological compounds)

Question 19

Novobiocin

Answer 19

3 parts: glycosidic sugar (noviose), coumarin ring system, benzamide side chain
Binds to DNA gyrase and can affect DNA supercoiling
Some anti-cancer properties