IID 05: Chemistry of Macrolides/Tetracycline/Clindamycin/Vancomycin/Misc Flashcards
Chemistry of Vancomycin
What bacteria does vancomycin target?
gram-positive infections – due to size, etc.
Chemistry of Vancomycin
Identify structural components of the glycopeptide vancomycin.
heptapeptide
- phenylglycine (3)
- tyrosine (2)
- asparagine
- valine
disaccharide component
Chemistry of Vancomycin
Draw the hydrogen-bonding interactions between vancomycin dimers and D-Ala-D-Ala
(mechanism of action).
- dimerization is head-to-tail
- sugars and chloro groups contribute to dimerization
- H-bond between backbones
- binding blocks transpeptidase
Chemistry of Vancomycin
What causes vancomycin resistance?
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)
Chemistry of Vancomycin
Provide a rationale for the spectrum of activity for vancomycin and similar lipoglycopeptides (telavancin, teicoplanin, and dalbavancin) toward gram-positive bacteria.
- alkyl groups in televancin and teicoplanin anchor to, and disrupt cell membrane
- group in dalbavancin induces cell membrane permeability
What does MurA (UDP-N-acetylglucosamine-3-enolpyruvyl transferase) do?
catalyzes an early step in peptidoglycan biosynthesis (building the bacterial cell wall)
- UDP-NAG + PEP → UDP-GlcNAc-enolpyruvate + Pi
What is fosfomycin?
phosphoenolpyruvate (PEP) analogue
- see notes to compare structures
What does fosfomycin do?
irreversibly inhibits MurA – but through a different mechanism than what the enzyme catalyzes with its PEP substrate
How is fosfomycin capable of a broad activity spectrum (ie. gram-positive and gram-negative bacteria)?
fosfomycin enters gram-positive and gram-negative bacteria through a glycerophosphate transporter
Describe the structural features of daptomycin.
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
Explain the mechanism of action of daptomycin.
daptomycin binds to cell membranes (calcium-dependent aggregation) and causes depolarization through pore formation
- ion leakage interrupts DNA, RNA, and protein synthesis
Protein Synthesis Inhibitors
antibiotics bind to 50S subunit
Chemistry of Macrolides
What are the main structural features of macrolides?
characteristic large lactone (cyclic ester) ring
Chemistry of Macrolides
What do macrolides bind to?
bind to 23S RNA of the 50S subunit and inhibit peptidyl transfer
Chemistry of Macrolides
Describe the structural features of erythromycin?
two sugars – one has mildly basic substituted amino group
Chemistry of Macrolides
How is the bitter taste of erythromycin masked? (2)
- 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)
Chemistry of Macrolides
What is erythromycin instability attributed to?
What minimizes this issue?
rapid acid-catalyzed intramolecular ketal formation primarily in the GI tract, leading to drug inactivation
- coated tablets minimize this issue
Chemistry of Macrolides
What are the 2nd generation erythromycin analogues?
- clarithromycin
- azithromycin
Chemistry of Macrolides
Describe the structural features of clarithromycin.
methyl ether (O–––) at position 6
Chemistry of Macrolides
Describe the structural features of azithromycin.
N-methyl group (N–––) at position 9a
Chemistry of Macrolides
What are the 3rd generation erythromycin analogues?
telithromycin (ketolide)
Chemistry of Macrolides
Describe the structural features of telithromycin.
- O== at position 3
- methyl ether (O–––) at position 6
- group with pyridine group at end at position 11
Chemistry of Macrolides
How is acid stability of 2nd and 3rd generation macrolides achieved?
by modification to substituents at positions 6 and/or 9 (limits nucleophilic attack)
Chemistry of Macrolides
Describe the pyridine group in telithromycin (3rd generation).
associated with some liver toxicity and antagonistic activity toward cholinergic receptors, but the drug is active against erythromycin-resistant bacteria
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
Chemistry of Macrolides
List other classes of antibiotics that share the same binding site that may also be affected
by macrolide resistance.
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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
Chemistry of Lincosamides
What are lincosamides?
weakly basic (pK a 7.5) and form clinically useful HCl salts against gram-positive bacteria
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
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%)
Chemistry of Lincosamides
Describe the mechanism of action of lincosamides toward inhibiting protein synthesis.
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Chemistry of Linezolid
What is linezolid?
orally bioavailable oxazolidinone
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
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)
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.
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
Protein Synthesis Inhibitors
antibiotics binding to 30S subunit
Chemistry of Tetracyclines
What are tetracyclines based on?
a partially reduced, highly functionalized naphthacene ring system
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
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
Chemistry of Tetracyclines
What are the various mechanisms for tetracycline chemical instability?
- epimerization
- base-catalyzed cleavage
- acid-catalyzed dehydration
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)
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)
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)
Chemistry of Tetracyclines
Which commonly prescribed tetracyclines is affected by metal chelation?
- tetracycline
- demeclocycline
- minocycline
- doxycycline
Chemistry of Tetracyclines
Which commonly prescribed tetracyclines is affected by epimerization?
- tetracycline
- demeclocycline
- minocycline
- doxycycline
Chemistry of Tetracyclines
Which commonly prescribed tetracyclines is affected by base-catalyzed cleavage?
(look at 6th position)
- tetracycline
- demeclocycline
Chemistry of Tetracyclines
Which commonly prescribed tetracyclines is affected by acid-catalyzed dehydration?
(makes tertiary carbocation intermediate)
- tetracycline
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
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
