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Anti-Infectives Exam 3 > Lecture 7 - Med Chem Antibiotics 2 > Flashcards

Lecture 7 - Med Chem Antibiotics 2 Flashcards

(46 cards)

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1
Q

Agents with an action site on 30S ribosomal subunit

A

Aminoglycosides

Tetracyclines

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2
Q

Agents with an action site on the 50S ribosomal subunit

A 
Erythromycin + other semi-synthetic macrolides
Lincosamides
Chloramphenicol
Streptogramins
Oxazolidinones
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3
Q

3 pharmacophoric 1,3-diaminoinositol moiety found in Aminoglycosides are…

A

Streptamine
2-deoxystreptamine
Spectinamine

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4
Q

Aminoglycoside info

A

freely soluble at all achievable pHs

are basic and form acid addition salts

not absorbed in significant amounts in GI track

excreted in active form in high conc

** V polar, accumulates in nephrons = nephrotoxicity + kidney failure***

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5
Q

When given orally, action is primarily confined to where for Aminoglycosides?

A

GI track

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6
Q

Aminoglycoside spectra

A

broad spectra but toxicity limits clinical use to severe infections by gram -

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7
Q

Aminoglycoside toxicities

A

Ototoxicity to functions mediated by 8th cranial nerve

ex. hearing loss, vertigo

can also lead to kidney tubular necrosis

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8
Q

Levels of protein binding ahminoglycosides?

A

Low lvls, widely distributed in extracellular fluids

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9
Q

Mechanism of action Aminoglycosides

A
  1. Bactericidal due to combo of toxicity
    • charge, enter bacterial cell walls…bind to - charge LPS and diffuse into walls in small amount
  3. uptake process inhibited by Ca and Mg ions, so dont take supplement w/ antibiotics
  4. drug will destroy semipermeability of cell membrane and more come in and cause death
  5. at increased conc, protein biosynthesis ceases
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10
Q

What portion of 30S do aminoglycosides bind?

A

Bind to 16S ribosomal RNA portion

impairing proof reading function

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11
Q

Bacterial Resistance Aminoglycosides

A
  1. compound modified outside the cell, poor uptake = resistance
  2. enzymes can acetylate the amino groups and phosphorylate/adenylate the hydroxyl groups which are essential to binding ribosomal proteins
  3. Anaerobic organisms such as Bacteroides are resistant, lac oxygen dependent transport to move drug across membrane
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12
Q

N-acylation aminoglycoside due to….

A

AAC-aminoglycoside acetylate

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13
Q

O-phosphorylation amino glycoside due to….

A

APH-aminoglycoside phosphorylase

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14
Q

O-adenylation amino glycoside due to….

A

ANT-aminoglycoside nucleotide transferase

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15
Q

Kanamycin

A

mixture of 3 components

2nd line for M.tuberculosis

only utilized to treat resistant organisms and used in combo with others

Parenteral form only

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16
Q

What is Kanamaycin unstable to?

A

R-factor enzymes

O-phosphorylated at C3, N-acetylated at C6

transformation products inactive antibiotically

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17
Q

Amikacin

A

made semi synthetically from kanamycin A

HABA moiety at N3 inhibits adenylation and phosphorylation in the distant amino sugar ring (C3/C2)…this is due to decreased binding to R-factor mediated enzymes

This change, strong enhanced potency and spectrum

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18
Q

Tobramycin

A

Lack C3 hydroxyl group = not substrate for APH(3)-1 = broader spectrum than kanamycin

Substrate at C2 by ANT, acetylation at C3 by AAC and C2 by AAC

widely used parenterally for difficult infections

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19
Q

Gentamicin

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A

Spectrum is enhanced as some of the functional groups serve as targets for R-factor

less $$

inactivated via C2 adenylation + acetylation at C6/C2

used in UTI, burns, some pneumonias, bone + joint infections by gram -

20
Q

Aminoglycoside incompatibility issue

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A

When combo w/ certain B-lactam, the two drugs react w/ each other so that N-acylation of C-1 of C1 of gentamicin by B-lactam takes plus..inactivaitng both

2 agents shouldn’t be mixed in same solution and admin in different tissue compartments (ie 1 in each arm)

21
Q

Streptomycin (STM)

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A

water soluble w/ basic properties

results in v poor absorption from GI tract and commonly given IM

22
Q

Streptomycin MOA

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A

inhibits protein synthesis, but addition effects on misreading of a mRNA template and membrane damage may contribute to bactericidal action of STM

23
Q

Streptomycin Metabolsim

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A
  1. metabolism impacted as major mech of resistance
  2. adenyltransferase catalyzes adenylation of C3 hydroxyl group to give O-3-adenylate and phosphotransferase turns same C-3 into 0-3-phosphorylate

results in metabolite that won’t bind to RNA

24
Q

Tetracycline MOA

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A

inhibits protein synthesis at ribosomal lvl leading to bacteriostasis

25
Tetracyclines info
1. Chelation: incompatibility w/ cadmic multivalent ion rich antacids and consumption of dairy products 2. IM = painful, cadmic with EDTA + buffered at acidic pH where chelation is less pronounced and watersolubility is higher. 3. old samples lose half of their potency due to epimerization
26
Semi-synthetic tetracyclines
1. Doxy- + minocycline = longer T1/2 2. both good oral bioavailability and given once a day 3. Absorption lowered by 20% coadmin w/ milk+food 4. Mino vestibular toxicities not shared with other tetracyclines
27
Macrolide info
1. safest abx in common se, URT + LRT + soft tissue 2. derived from large lactone ring 3. contains 2 or more characteristic sugars ( cladinose + desosamine) 4. weakly basic amino group in sugars 5. salt form = improve water solubility
28
2 characteristic sugars of Macrolide?
Cladinose and Desosamine
29
Chemical properties of Macrolides
1. chemical instability of earlier ones due to acid-catalyzed internal metal formation resulting in bio-inactivation Minimized by admin in coated tabs
30
Macrolides MOA
Bind to 23S rRNA in polypeptide exit tunnel adjacent to peptides transfer center in 50S ribosomal unit Peptide formation/elongation step is inhibited
31
Extensive cross resistance between macrolides because....
they bind in the same vicinity in 50S ribosomal subunit
32
What mediates bacterial resistance through R-factor enzymes for macrolides?
Methylation of specific guanidine residues on their specific ribosomal RNAs to inhibit/reduce macrolide binding
33
Clarithromycin info
C6 hydroxyl group converted to C6 methoxy to prevent internal attack on keto group to form metal Methoxy group offers more lipophilicity to compound + prevents metal formation This gives better blood lvls but also less gi upset
34
Azithromycin
conversion in erythromycin or clarithromycin ....N-methyl group inserted between C9/C10 and carbonyl moiety is absent doesn't form metal intermediate, more aid stable, considerable long life
35
Lincosamide MOA
bind to 50S ribosomal sub particle at site partly overlapping w/ macrolide binding site and are mutually cross-resistant with macrolides similar MOA to macrolides
36
Chemical properties Lincosamides
Weakly basic, salt form w/ acid improve solubility
37
Metabolism Lincosamides
extensive liver metabolism resulting primarily in N-demethylation N-desmethyl analog retains biological activity
38
Lincomycin + Clindamycin are....
structurally related SN2 run on Lincomycin replaces OH group w/ CL group with inversion of configuration R C7 to S C7 Clinda more potent + lipophilic & better absorbed following oral admin
39
Chloramphenicol info
neutral compound poor/mod solubility. improved by forming prodrug 2 chiral centers, 4 stereoisomers possible givenly orally, rapidly absorbed + short 1/2 life
40
Which stereoisomers of Chloramphenicol are significantly active?
1R, 2R
41
Chloramphenicol MOA
binds 50S sub particle region. resistance developed through acetylation of free OH groups by R-factor mediated enzymes. acetylated production no longer binds ribosomes and is inactive
42
Streptogramins
VRSA and VRE usage synergy observed when using A + B
43
Quinuprisint + Dalfoprisitn
Synercid, 30:70 ratio combo streptogrmains for IV Dalfoprisitin binds 70S particle of A/P sites Quinupristin binds A/P site too drugs are bacteriostatic when admin solo, bactericidal when admin together Dalfoprisitn creates high affinity binding site for quinupristin
44
Linezolid info
1. effective against gram + 2. Gram - intrinsically resistant due to endogenous efflux pumps 3. well absorbed orally, comes as tab, iv, suspenison
45
Linezolid MOA
binds to 50S sub particle preventing the formation of functional initiation complex
46
Linezolid metabolism
significant oxidative metabolism occurs by oxidation of morpholine ring. Metabolites don't retain antibacterial activity

Anti-Infectives Exam 3 (7 decks)

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