iPTX3 EX2 L2 (MEDCHEM ANTIMICROBIALS PT 1 -> B-LACTAMS + VANCO) (CHENG)

Development of antibiotics has decreased infant mortality rate by a factor of _________

A. 5

B. 10

C. 15

D. 18

B. 10

In the past fifty years, antibiotic development has extended the developed country life expectancy by _______ years

A. 20

B. 25

C. 30

D. 35

C. 30

Examples of bacteriostatic drugs? (six)

1. Chloramphenicol

2. Erythromycin

3. Clindamycin

4. Sulfonamides

5. Trimethoprim

6. Tetracyclines

Examples of bactericidal drugs? (six)

1. Aminoglycosides

2. Beta-lactams

3. Vancomycin

4. Quinolones

5. Rifampin

6. Metronidazole

5 mechanisms of action of antibiotics?

1. Inhibition of cell wall synthesis

2. Disruption of cell membrane structure or function

3. Inhibition of protein synthesis

4. Inhibition of nucleic acid synthesis, structure, or function

5. Block metabolic reaction

Cell wall synthesis inhibiting antibiotics examples? (four)

1. Penicillin

2. Bacitracin

3. Cephalosporins

4. Vancomycin

Disruption of cell membrane function antibiotic example? (one)

1. Polymyxin

Inhibition of nucleic acid synthesis antibiotics examples? (three)

1. Rifamycin (transcription)

2. Quinolones (DNA replication)

3. Metronidazole

Inhibition of protein synthesis antibiotics examples? (four)

1. Tetracyclines

2. Erythromycin

3. Streptomycin

4. Chloramphenicol

Action as antimetabolites antibiotics examples? (two)

1. Sulfonilamide

2. Trimethoprim

B-lactams are a ____ membered ring

A. Three

B. Four

C. Five

D. Six

B. Four

T/F: The four-membered B-lactam ring is the key structural feature of penicillins.

True

T/F: B-lactam rings fuse to become five-membered thiazolidine rings, which are *less* reactive than monocyclic B-lactams.

False; more reactive than monocyclic B-lactams

T/F: Penicillins are susceptible to bacterial metabolism and inactivation by amidases and lactamases.

True

Core structure of the penicillins?

6-aminopenicillanic acid (6-APA)

Core structure of the cephalosporins?

7-aminocephalanosporanic acid

Core structure of the monobactams?

3-amino-4-methylmonobactamic acid

Core structure of the carbapenems?

3-hydroxymethylcarbapenemic acid

How many rings in a 6-aminopenicillanic acid (the core structure of penicillin)?

A. 1

B. 2

C. 3

D. 4

B. 2

Define the cell wall of bacteria

Rigid outer layer; unique to bacterial species. Completely surrounds cytoplasmic membrane.

Role of the cell wall in bacteria

Maintain cell shape and integrity, prevent cell lysis from high osmotic pressure.

Bacterial cell wall is composed of what?

Complex, cross-linked polymer of polysaccharides and polypeptides, peptidoglycan

Cross-links between what two alternating amino sugars give the cell wall its structural rigidity?

N-acetylglucosamine (NAG)

N-acetylmuramic acid (NAM)

T/F: Beta-lactam antibiotics *covalently* bind to the active site of PBPs.

True

Mechanism by which cell wall inhibition calls lysis?

Cells swell and burst from water entering the cell

Penicillin reacts with what enzyme specifically, leading to an irreversible covalent bond formation that weakens the cell wall?

Transpeptidase enzyme

T/F: Gram negative bacteria have a hydrophobic outer membrane that is NOT present in gram positive bacteria.

True

Why are gram negative bacteria overall less susceptible to penicillins? (four)

Hydrophobic outer membrane prevents access to the cell wall; penicillins can only cross via porins

Also, gram negative bacteria have high levles of lactamase

And, transpeptidase enzyme in gram negative bacteria might have lower affinity for penicillins

Finally, efflux mechanisms pump penicillins out of periplasmic space in gram negative bacteria

What is the target of penicillins as antibiotics?

A. Lactamase

B. Transpeptidase

C. Beta-lactam

D. 6-APA

B. Transpeptidase

What is the mechanism of action of penicillin?

A. Inhibit protein synthesis

B. Inhibit folic acid synthesis

C. Inhibition of cell wall synthesis

D. Disruption of cell membrane structure or function

E. Inhibition of nucleic acid synthesis, structure or function

C. Inhibition of cell wall synthesis

Which of the following is NOT a reason why penicillin is less active against gram-negative bacteria than gram-positive bacteria?

A. Gram-negative bacteria have a hydrophobic outer membrane

B. Gram-negative bacteria have a thicker cell wall

C. Gram-negative bacteria release more B-lactamase

D. Gram-negative bacteria possess efflux mechanisms that pump penicillin out

B. Gram-negative bacteria have a thicker cell wall

Carboxylic acid binds as the __________ ion in penicillins

Carboxylate ion

T/F: Bicyclic system increases B-lactam ring strain, which is related to activity.

True

3 problems associated with Penicillin G?

1. Sensitive to stomach acids

2. Sensitive to B-lactamases, enzymes which hydrolyze the B-lactam ring

3. Limited range of activity

Spectrum of activity for Penicillin G?

Active against Gram + rods

Active against some gram - cocci

4 important characteristics of Penicillin V (oral penicillin)

1. Acid stability, orally active

2. Still sensitive to B-lactamases

3. Slightly less active than Pen G

4. Allergic reactions!

What is unique about the semi-synthetic penicillins? (what kind of group did they add?

These are ampicillin, oxacillin;

Added electron withdrawing groups

What is the role of a steric shield?

Decreasing beta-lactamase susceptibility

If the shield can block access of penicillin to the active site of the enzyme (by introducing bulky groups to the side chain) we can decrease B-lactamase susceptibility

Size of shield important!

One way to increase chemical stability and improve oral administration of penicillins?

Add electron withdrawing group

Two ways to reduce B-lactamase susceptibility of penicillins?

Use steric shields

Add B-lactamase inhibitor

T/F: Clavulanic acid is an powerful irreversible inhibitor of B-lactamases (suicide substrate).

True

What is not the limitation of penicillin G?

A. Sensitive to stomach acid

B. Sensitive to B-lactamase

C. Limited activity on gram-negative

D. Bactericidal

D. Bactericidal

What is the function of beta-lactamase inhibitors?

A. Inhibit protein synthesis

B. Inhibition of cell wall synthesis

C. Disruption of cell membrane structure or function

D. Improve the stability of penicillins

B. Inhibition of cell wall synthesis

Which one is NOT an effective way to improve the properties of penicillins?

A. Adding electronic-withdrawing groups in the sidechain

B. Using with clavulanic acid together

C. Modifying sidechain (adding NH2, COOH, or Urea groups)

D. Removing carboxylic acid group connecting the thiazolidine ring

D. Removing carboxylic acid group connecting the thiazolidine ring

How to increase penicillins range of activity?

Add NH2, COOH group

Side chain adjustments

Where were cephalosporins initially discovered?

Sardinian sewer water fungal colony

T/F: Cephalosporins are relatively stable in acid and highly resistant to beta-lactamase.

True

How many rings do cephalosporins have?

A. 1

B. 2

C. 3

D. 4

B. 2

Possible modifications in cephalosporins? (three)

1. 7-acylamino side chain

2. 3-acetoxymethyl side chain

3. Substitution at C7

What is the target of cephalosporin as antibiotics?

A. Lactamase

B. Transpeptidase

C. Beta-lactam

D. 6-APA

B. Transpeptidase

What is the mechanism of action of cephalosporins?

A. Inhibit protein synthesis

B. Inhibit folic acid synthesis

C. Inhibition of cell wall synthesis

D. Disruption of cell membrane structure or function

E. Inhibition of nucleic acid synthesis, structure or function

C. Inhibition of cell wall synthesis

Which property increase from 1st generation to the 4th generation cephalosporins?

A. Activity on gram + bacteria

B. Activity on gram - bacteria

B. Activity on gram - bacteria

What is the major difference between the core structure of Cephalosporins and penicillins?

A. The number of rings

B. The size of rings

C. One with sulfur and the other does not have sulfur

D. Hydrogen cis configuration

B. The size of rings

Carbapenems have a ____ membered ring system

A. 3

B. 4

C. 5

D. 6

C. 5

T/F: The carbapenem fused B-lactam ring and 5-membered ring system differs from penicillins in that it is unsatured (double bond at C-2/C-3) and contains a carbon as opposed to a sulfur atom.

True

T/F: Carbapenems are used typically for known or suspected MDR bacteria.

True

Why do we administer imipenem with cilastatin?

Imipenem is easily hydrolyzed by dehydropeptidase; *cilastatin inhibits peptidase*

What is the function of cilastatin in Tienam?

A. Beta-lactamase inhibitor

B. Peptidase inhibitor

C. Cell wall synthesis inhibitor

D. Penicillin binding proteins inhibitor

B. Peptidase inhibitor

What is the major difference between the core structure of carbapenems and penicillins?

A. The number of rings

B. The size of rigns

C. The sulfur position

D. One with beta-lactam ring and the other does not have beta lactam

C. The sulfur position

T/F: Monobactams have a monocyclic B-lactam ring and are resistant to B-lactamases.

True

T/F: Monobactams cover most aerobic gram - bacteria, *including* P. aeruginosa.

True

Aztreonam is selectively active against _______

A. Gram positive bacteria

B. Gram negative bacteria

B. Gram negative bacteria

What is the major difference between the core structure monobactam and penicillins

A. The number of rings

B. One with beta-lactam ring and the other does not have beta-lactam

A. The number of rings

T/F: Vancomycin is called a glycopeptide, meaning that it is a cyclic peptide with sugar residues attached to it.

True

T/F: Vancomycin cannot be used to treat gram negative bacteria.

True

We use vancomycin to treat ______

A. Anaerobic gram positive bacteria

B. Aerobic gram positive bacteria

C. Anaerobic gram negative bacteria

D. Aerobic gram negative bacteria

B. Aerobic gram positive bacteria

But it is active against some anaerobes, including C. dificile

Polymyxin class? (aside from polymyxins)

Lipopeptide

T/F: Polymyxin's general structure consists of a cyclic peptide with a long hydrophobic tail.

True

MOA of polymxin?

Disrupt the structure of bacterial cell membranes by interacting with its phospholipids

T/F: Polymyxins are selective for gram + bacteria.

False; only active against gram - bacteria (because gram + does not have a cell membrane)

Vancomycin is similar to penicillin G EXCEPT

A. Inhibition of cell wall synthesis

B. They are both beta-lactam inhibitors

C. Administered intravenously

D. Selectively active against Gram+ bacteria

B. They are both beta-lactam inhibitors

What is the mechanism of action of Polymyxin?

A. Inhibit protein synthesis

B. Inhibit folic acid synthesis

C. Inhibition of cell wall synthesis

D. Disruption of cell membrane structure or function

E. Inhibition of nucleic acid synthesis, structure, or funtion

D. Disruption of cell membrane structure or function