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PHRM 111 – IID > IID 05: Chemistry of Macrolides/Tetracycline/Clindamycin/Vancomycin/Misc > Flashcards

IID 05: Chemistry of Macrolides/Tetracycline/Clindamycin/Vancomycin/Misc Flashcards

(50 cards)

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1
Q

Chemistry of Vancomycin

What bacteria does vancomycin target?

A

gram-positive infections – due to size, etc.

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2
Q

Chemistry of Vancomycin

Identify structural components of the glycopeptide vancomycin.

A

heptapeptide

  • phenylglycine (3)
  • tyrosine (2)
  • asparagine
  • valine

disaccharide component

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3
Q

Chemistry of Vancomycin

Draw the hydrogen-bonding interactions between vancomycin dimers and D-Ala-D-Ala
(mechanism of action).

A
  • dimerization is head-to-tail
  • sugars and chloro groups contribute to dimerization
  • H-bond between backbones
  • binding blocks transpeptidase
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4
Q

Chemistry of Vancomycin

What causes vancomycin resistance?

A

replacement of the terminal D-Ala residue with D-lactate eliminates a single hydrogen bond between vancomycin and the peptidoglycan cell wall

  • vancomycin-resistant Enterococcus (VRE)
  • vancomycin-resistant S. aureus (VRSA)
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5
Q

Chemistry of Vancomycin

Provide a rationale for the spectrum of activity for vancomycin and similar lipoglycopeptides (telavancin, teicoplanin, and dalbavancin) toward gram-positive bacteria.

A
  • alkyl groups in televancin and teicoplanin anchor to, and disrupt cell membrane
  • group in dalbavancin induces cell membrane permeability
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6
Q

What does MurA (UDP-N-acetylglucosamine-3-enolpyruvyl transferase) do?

A

catalyzes an early step in peptidoglycan biosynthesis (building the bacterial cell wall)

  • UDP-NAG + PEP → UDP-GlcNAc-enolpyruvate + Pi
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7
Q

What is fosfomycin?

A

phosphoenolpyruvate (PEP) analogue

  • see notes to compare structures
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8
Q

What does fosfomycin do?

A

irreversibly inhibits MurA – but through a different mechanism than what the enzyme catalyzes with its PEP substrate

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9
Q

How is fosfomycin capable of a broad activity spectrum (ie. gram-positive and gram-negative bacteria)?

A

fosfomycin enters gram-positive and gram-negative bacteria through a glycerophosphate transporter

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10
Q

Describe the structural features of daptomycin.

A

cyclic lipopeptide fermentation product active against gram-positive bacteria (capable of traversing cell wall)

  • decanoate
  • L-Trp
  • L-Asn
  • L-Asp (2)
  • L-Kyn
  • L-Thr
  • Gly (2)
  • L-Orn
  • L-Asp
  • D-Ala
  • L-Ser
  • 3MeGlu
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11
Q

Explain the mechanism of action of daptomycin.

A

daptomycin binds to cell membranes (calcium-dependent aggregation) and causes depolarization through pore formation

  • ion leakage interrupts DNA, RNA, and protein synthesis
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12
Q

Protein Synthesis Inhibitors

A

antibiotics bind to 50S subunit

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13
Q

Chemistry of Macrolides

What are the main structural features of macrolides?

A

characteristic large lactone (cyclic ester) ring

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14
Q

Chemistry of Macrolides

What do macrolides bind to?

A

bind to 23S RNA of the 50S subunit and inhibit peptidyl transfer

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15
Q

Chemistry of Macrolides

Describe the structural features of erythromycin?

A

two sugars – one has mildly basic substituted amino group

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16
Q

Chemistry of Macrolides

How is the bitter taste of erythromycin masked? (2)

A
  • non-hydrogen R-substituted erythromycins are prodrugs – masks bitter taste and/or enhances stability in the stomach (ester linkage is hydrolyzed to activate)
  • salt formation with some acids increases solubility (ie. lactobionate), and others decrease solubility (ie. stearate and laurylsulfate)
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17
Q

Chemistry of Macrolides

What is erythromycin instability attributed to?
What minimizes this issue?

A

rapid acid-catalyzed intramolecular ketal formation primarily in the GI tract, leading to drug inactivation

  • coated tablets minimize this issue
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18
Q

Chemistry of Macrolides

What are the 2nd generation erythromycin analogues?

A
  • clarithromycin
  • azithromycin
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19
Q

Chemistry of Macrolides

Describe the structural features of clarithromycin.

A

methyl ether (O–––) at position 6

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20
Q

Chemistry of Macrolides

Describe the structural features of azithromycin.

A

N-methyl group (N–––) at position 9a

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21
Q

Chemistry of Macrolides

What are the 3rd generation erythromycin analogues?

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A

telithromycin (ketolide)

22
Q

Chemistry of Macrolides

Describe the structural features of telithromycin.

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A
  • O== at position 3
  • methyl ether (O–––) at position 6
  • group with pyridine group at end at position 11
23
Q

Chemistry of Macrolides

How is acid stability of 2nd and 3rd generation macrolides achieved?

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A

by modification to substituents at positions 6 and/or 9 (limits nucleophilic attack)

24
Q

Chemistry of Macrolides

Describe the pyridine group in telithromycin (3rd generation).

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A

associated with some liver toxicity and antagonistic activity toward cholinergic receptors, but the drug is active against erythromycin-resistant bacteria

25
Chemistry of Macrolides Describe the mechanism of action of macrolides toward inhibiting protein synthesis.
drugs bind to 23S RNA of the 50S subunit & inhibit peptidyl transfer
26
Chemistry of Macrolides List other classes of antibiotics that share the same binding site that may also be affected by macrolide resistance.
–
27
Chemistry of Lincosamides Whata re the two main structural features of lincosamides?
thiomethyl amino-octoside (O-thio-lincosamide) linked through an amide to an n-propyl substituted N-methylpyrrolidyl carboxylic acid
28
Chemistry of Lincosamides What are lincosamides?
weakly basic (pK a 7.5) and form clinically useful HCl salts against gram-positive bacteria
29
Chemistry of Lincosamides Where do lincosamides bind?
binds to the same place as macrolides – partly overlap with the macrolide binding site on the 50S ribosomal subunit and experience mutual cross-resistance
30
Chemistry of Lincosamides Describe the key structural difference that has clinical relevance between lincomycin and clindamycin.
incomycin has hydroxyl group, while clindamycin has chlorine substitution for this group to increase lipophilicity and oral bioavailability (30 vs. 90%)
31
Chemistry of Lincosamides Describe the mechanism of action of lincosamides toward inhibiting protein synthesis.
–
32
Chemistry of Linezolid What is linezolid?
orally bioavailable oxazolidinone
33
Chemistry of Linezolid Identify functional groups of linezolid.
- fluorine atom, acetamide group, and morpholine group (nitrogen is electron-donating) contribute to antibiotic potency/50S ribosomal subunit binding (50S:linezolid complex) - substituted fluorophenyl ring of linezolid participates in parallel-displaced pi-pi stacking with cytosine-2487
34
Chemistry of Linezolid Describe the mechanism of action of linezolid toward inhibiting protein synthesis.
oxazolidinones inhibit the initiation of protein synthesis by preventing the formation of a functional initiation complex (unlike other protein synthesis inhibitors that act after a functional initiation complex is formed)
35
Chemistry of Linezolid What is is resistant to linezolid?
gram-negative bacteria are inherently resistant to linezolid due to endogenous efflux pumps that prevent drug from accumulating in cells - clinical resistance to oxazolidinones is generally caused by a mutation in the 23S rRNA of the 50S subunit – overlaps with macrolides, etc.
36
Chemistry of Linezolid Note the potential for drug-drug interactions affecting MAO activity.
linezolid is structurally similar to the monoamine oxidase inhibitor toloxatone and has a similar effect - drug interaction with SSRIs/antidepressants
37
Protein Synthesis Inhibitors
antibiotics binding to 30S subunit
38
Chemistry of Tetracyclines What are tetracyclines based on?
a partially reduced, highly functionalized naphthacene ring system
39
Chemistry of Tetracyclines How are tetracyclines amphoteric drugs?
- tertiary amino group provides for the basic functionality of tetracyclines - resonating systems of tetracyclines contribute to acidic groups - tetracyclines are generally administered as water-soluble HCl salts
40
Chemistry of Tetracyclines Describe how metal chelation affects drug solubility.
- tetracycline salts of polyvalent metal ions such as Fe2+, Ca2+, Mg2+, and Al3+ are insoluble at neutral pH - food and dairy products can decrease tetracycline absorption by 50% - tetracyclines can accumulate in calcium-rich structures (ie. teeth) and cause discolouration (yellow) – inextreme cases, tetracyclines can mechanically weaken bone structure, therefore they are not normally given to children
41
Chemistry of Tetracyclines What are the various mechanisms for tetracycline chemical instability?
- epimerization - base-catalyzed cleavage - acid-catalyzed dehydration
42
Chemistry of Tetracyclines What is the mechanism of epimerization?
- alpha-stereo configuration of the C-4 dimethylamino group is essential for tetracycline activity - tetracycline exhibits epimerization at the C-4 position - at equilibrium, the ratio of diastereomers is approximately 1:1 - ie. tetracycline to enol form to 4-epitetracycline (inactive)
43
Chemistry of Tetracyclines What is the mechanism of base-catalyzed cleavage?
- base-catalyzed cleavage of the C ring (bond 11-11a) occurs in alkaline solutions at or above pH 8.5 to form an inactive lactonic product - base-catalyzed cleavage occurs in tetracyclines that contain a benzylic hydroxyl group at C-6 - ie. tetracycline to isotetracycline (inactive enol form) and isotetracycline (inactive keto form)
44
Chemistry of Tetracyclines What is the mechanism of acid-catalyzed dehydration?
- dehydration occurs in tetracyclines that contain a benzylic (3 ̊ > 2 ̊) hydroxyl group at C-6 - formation of the naphthalene derivative (yields deeper colour) is energetically favourable - ie. tetracycline to anhydrotetracycline (inactive)
45
Chemistry of Tetracyclines Which commonly prescribed tetracyclines is affected by metal chelation?
- tetracycline - demeclocycline - minocycline - doxycycline
46
Chemistry of Tetracyclines Which commonly prescribed tetracyclines is affected by epimerization?
- tetracycline - demeclocycline - minocycline - doxycycline
47
Chemistry of Tetracyclines Which commonly prescribed tetracyclines is affected by base-catalyzed cleavage?
(look at 6th position) - tetracycline - demeclocycline
48
Chemistry of Tetracyclines Which commonly prescribed tetracyclines is affected by acid-catalyzed dehydration?
(makes tertiary carbocation intermediate) - tetracycline
49
Chemistry of Tetracyclines Describe the mechanism of action of tetracyclines toward inhibiting protein synthesis.
- tetracyclines bind to rRNA in the 30S subparticle and prevents productive aminoacyl-tRNA docking onto the ribosome - protein synthesis inhibition results in peptide chain termination - dimethylamino group and C-3 oxygen interact with phosphate - more hydrophobic tetracyclines (ie. minocycline) also disrupt cytoplasmic membrane function, causing leakage of essential cellular components from the cell
50
Chemistry of Tetracyclines Describe the glycylcycline (ie. tigecycline) structure and its clinical impact.
- efforts to find tetracyclines capable of avoiding resistance mechanisms led to the discovery of glycylcyclines - C-9 glycylamido substitution in tigecycline causes 5x better ribosome binding than what is found for the minocycline parent compound - C-9 substituent decreases the chance of clinical resistance issues

PHRM 111 – IID (20 decks)

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