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Spring 2025 Therapeutics V > Exam 1- Cushman Lec 1- Bacterial Cell wall + Beta Lactams > Flashcards

Exam 1- Cushman Lec 1- Bacterial Cell wall + Beta Lactams Flashcards

1
Q

How does the structure of the cell wall in Gram (+) bacteria differ from Gram (-) bacteria?

A

Gram (+):
-Drugs penetrate the outer layers of cell wall effectively
-Bacterial membrane is the main barrier
-B-lactamases excreted through cell wall to external environment
-B lactamases produced in larger quantities
-Thick peptidoglycan layer
-Have 1 membrane
-Peptidoglycan residue is replaced by L-lysine residue (COOH is replaced with H)
-Peptidoglycan is cross-linked by a bridge between the L-Lys strand and the terminal D-Ala of a second molecule

Gram (-):
-Outer membrane excludes drugs, preventing penetration
-Porins in outer membrane allow some drugs to pass
-B-lactamases are confined to periplasmic space
-Thin peptidoglycan layer
-Have 2 membranes (inner + outer) with periplasmic space between -have a more complex wall that is lipoidal
-Peptidoglycan contains meso-diaminopimelic acid residue (DAP)
-Peptidoglycan is cross-linked by a bridge between DAP residue of one strand and the terminal D-Ala of another

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2
Q

What is the role of beta lactamases?

A

Hydrolyze beta lactam and inactivate the drugs

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3
Q

Which enzyme is responsible for cross-linking peptidoglycan strands?

A

Transpeptidase

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4
Q

How does transpeptidase cross-link peptidoglycan strands?

A

-Covalent bond

-Creates a Gly bridge between:
Gram (-): DAP residue of one strand and D-Ala of another
Gram (+): L-Lys strand of one and terminal D-Ala of another

-Transpeptidase active site has a serine residue (CH2OH)

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5
Q

Why is cross-linking of peptidoglycan strands important?

A

Confers strength to the bacterial cell wall

-cell wall will lyse and the bacteria will die without it

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6
Q

What well-known antibiotic is a beta-lactamase?

A

Penicillin

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7
Q

What is the mechanism of action of beta-lactam antibiotics?

A

Inhibit the transpeptidases that cross-link the peptidoglycan strands in the bacterial cell wall together

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8
Q

How do beta-lactam antibiotics inhibit peptidglycan?

A

They acylate the transpeptidase Ser residue in the enzyme active site to form a stable product

-this inactivates the transpeptidase and inhibits cross-linking, causing a defective bacterial cell wall

-cell wall is now subject to osmotic stress and the bacterial cell lyses

(see next notecard)

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9
Q

How does penicillin fool the transpeptidase into believing it is a peptidoglycan?

A

-Causes the transpeptidase to think it is a D-Ala-D-Ala residue at the end of a peptidoglycan
*peptidoglycan attacks the double bonded O just like it does in peptidoglycan (carbonyl)

-Forms a tetrahedral intermediate
*electrons move from H to O, forming another double bonded O (carbonyl)
**this breaks the four-membered ring

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10
Q

Why are penicillins/ beta-lactams reactive?

A

They have a four-membered ring
*this causes a lot of ring string and therefore, reactivity

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11
Q

What are the mechanisms of resistance that can occur against beta-lactams?

A

Decreased cellular uptake of the drug

Mutation of the penicillin-binding proteins that decreases their affinity for penicillins

Presence of an efflux pump that pumps antibiotics out of the cell

Induction/elaboration of bacterial B-lactamases that catalyze the hydrolysis of the B-lactam moiety
**note that this resistance mechanism is basically the same thing as the moa mechanism. Carbonyl is attacked, forms intermediate, ring structure breaks
–creates a regenerated B-lactamase and unstable hydrolyzed penicillin

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12
Q

What percent of the US population is allergic to B-lactams?

A

6-8%

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13
Q

What causes the allergenicity seen with B-lactams?

A

The drug acts as a hapten

-acylates host proteins, raising antibodies, and resulting in an allergic reaction

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14
Q

If a person is allergic to one penicillin can they be given another?

A

NO

cross-sensitivity is common, so if a person has an allergy to one B-lactamase, they are likely to have an allergy to another

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15
Q

What tests are available to test for B-lactam allergy?

A

Topical flare and wheal tests

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16
Q

Under which conditions do penicillins degrade?

A

Acidic and Basic

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17
Q

How does pencillin degrade under acidic conditions?

A

-The side chain has echimeric assistance (participates in mechanism of reaction to assist hydrolysis)

-Side chain carbonyl attacks the main carbonyl to form a five-membered ring

*Penicillin breaks down to Penicilloic acid

*Note that the nucleophilicity of the R on the side chain determines the reactivity. If electron attracting (electronegative) the O is less nucleophilic and penicillin is more stable. If electron-donating, the O is more nucleophilic and less stable (cannot be given po)

-Creates a penillic acid

-Also can create a penicillenic acid

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18
Q

How does penicillin degrade under basic conditions?

A

OH- group attacks main carbonyl and creates Penicilloic acid

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19
Q

True or False: Penicillin hydrolysis products have antibiotic activity

A

False
-they have to antibiotic activity

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20
Q

True or False: Hydrolysis of the B-lactam is irreversible

A

True
-once the 4-membered ring is opened, it cannot close again

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21
Q

True or False: Electronegative substituents on the side chain carbonyl reduce the nucleophilicity of the side chain and makes the B-lactam more stable

A

True

-the penicillin is stabilized against hydrolysis under acidic conditions
-the first step in the hydrolysis reaction is decelerated

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22
Q

What element present in the side chain will make it more electronegative, and therefore stabilize the penicillin?

A

O

-Penicillin V is more stable than Penicillin G because V has an extra oxygen in its side chain which is electronegative and decreases the nucleophilicity of the main carbonyl

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23
Q

What pH is best for penicillin storage?

A

6-6.8

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24
Q

What molecules can catalyze penicillin degradation reactions, and should therefore be kept away from penicillin solutions?

A

Heavy metal ions

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25
Q

How does lipophilicity of the penicillin side chain affect protein binding?

A

More lipophilic side chains result in more protein binding

26
Q

How does protein binding affect the action of B-lactams?

A

Protein binding reduces bioavailability
-reduces the effective concentration of the free drug

27
Q

Penicillins are excreted by which routes?

A

Renal
Biliary

28
Q

For penicillins excreted by the kidneys, what percent of excretion is glomerular vs tubular?

A

Glomerular filtration: 10%
Tubular secretion: 90%

29
Q

How is penicillin excretion affected by kidney disease/failure?

A

Penicillin half-life increases

30
Q

What are the 2 mechanisms of tubular secretion?

A

One for anions and one for cations

*Note that penicillins are anions

31
Q

How does probenecid affect penicillin excretion?

A

Penicillins are anionic and so is probenecid

-these two drugs compete with each other for secretion mechanisms
-therefore, when probenecid is administered with penicillin it increases the half-life of penicillin

32
Q

What are the 5 nomenclatures to know for B-Lactam ring systems?

A

These are added to the four-membered ring of penicillins:

Penam (5-membered ring with S and no double bond)

Penem (5-membered ring with S + double bond)

Carbapenem (5-membered ring with no S but has a double bond)

Cephem (6-membered ring with S + double bond)

Monobactam (no extra ring, just NH)

33
Q

What are the B-lactam sensitive penicillins?

A

Benzylpenicillin (Penicillin G)

Phenoxymethyl Penicillin (Penicillin V)

34
Q

What points are important to know about Benzylpenicillin (Penicillin G)?

A

Works on: Gram + cocci
B-lactam sensitivity: Yes
Admin: Parenteral
Precautions: In individuals with history of allergies/asthma

35
Q

What is the main difference between Penicillin G and V?

A

V is more stable in acid (can give po)
-due to extra oxygen on side chain (more electrophilic)

36
Q

What are the B-lactamase-resistant parenteral penicillins?

A

Methicillin
Nafcillin

37
Q

What causes methicillin to be resistant to B-lactamase?

A

Steric hinderance

-unable to have nucleophilic attack by the enzyme on the B-lactam carbonyl

38
Q

What are important points to know about methicillin?

A

-Unstable to acid in the stomach, must be administered by injection
-Discontinued due to resistance

39
Q

Why is methicillin so unstable in stomach acid?

A

The oxygen on the side chain, instead of reducing electronegativity of the main carbonyl, increases it

-oxygen in the side chain moves electrons to the carbonyl and makes it more electronegative

-this is due to the resonance effect

39
Q

What is the most important bug to remember that is resistant to methicillin?

A

MRSA
(methicillin-resistant staphylococcus aureus)

-because of mutation in transpeptidase

40
Q

What gene codes for the mutated penicillin-binding protein (transpeptidase) in MRSA?

A

mecA
(methicillin resistance gene)

41
Q

What penicillin binding protein is coded for by mecA?

A

PBP2A

*this is the protein found in MRSA
*it can cross-link peptidoglycan but does not react with methicillin and many other B-lactams

42
Q

What are the important points to remember about Nafcillin?

A

-Not sensitive to beta lactamase
-Slightly more stable than methicillin in acid

43
Q

What are the B-lactamase-Resistant oral penicillins?

A

Oxacillin
Cloxacillin
Dicloxacillin

44
Q

Why are oxacillin, cloxacillin, and dicloxacillin B-lactamase resistant?

A

They all have an isoxazole structure and large 6-membered ring that sterically hinders the carbonyl

45
Q

Which B-lactamase resistant penicillin is the only one still used orally?

A

Dicloxacillin

46
Q

What are the B-Lactamase-Sensitive, Broad-Spectrum, Oral Penicillins?

A

Ampicillin
Amoxicillin

47
Q

What organisms are sensitive to ampicillin?

A

Gram-
(Salmonella, Shegella, Proteus mirabilis, Escherichia coli, Haemophilis influenzae, Neisseria gonorrhea)

48
Q

How is ampicillin able to be transported into Gram - bacteria?

A

The porin channels are hydrophilic and transport ionic compounds

-ampicillin has a charged amino group at physiological pH, allowing it to be transported through porins

49
Q

Why is ampicillin stable in acid?

A

The amino group is protonated in the stomach
-the charged nitrogen group becomes more electron-attracting
-this decreases nucleophilicity of the carbonyl and it does not participate in ring-opening

50
Q

What points are important to remember about amoxicillin?

A

-Analog of ampicillin
—only difference is the addition of a hydroxyl group to the aromatic ring

**Better oral absorption than ampicillin

51
Q

What are the B-lactamase inhibitors?

A

Clavulanic Acid

Sulbactam

Tazobactam

Avibactam

52
Q

When are B-lactamase inhibitors used?

A

In combination with B-lactamase-sensitive penicillins

-enhance the activity of these penicillins against resistant strains

53
Q

What is the MOA of the B-lactamase inhibitors?

A

Acylate the serine hydroxyl group in the active site of the B-lactamase

54
Q

What is the brand name of Potassium Clavulanate + Amoxicillin?

A

Augmentin

55
Q

What is the brand name of Sulbactam + Ampicillin?

A

Unasyn

56
Q

What is the brand name of Sulbactam + Pipericillin?

A

Zosyn

57
Q

What is the bran name of Avibactam + Ceftazidime?

A

Avycaz

58
Q

What is the B-Lactam-Sensitive, Broad-Spectrum, Parenteral Penicillin?

A

Piperacillin

59
Q

What bacteria is piperacillin active against?

A

Gram -
Gram +

60
Q

Why does piperacillin have enhanced potency over the B-lactam-sensitive oral penicillins?

A

The added side chain fragment on piperacillin resembles a longer section of the peptidoglycan chain than ampicillin

Spring 2025 Therapeutics V (13 decks)

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