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

Lecture 7 - Med Chem Antibiotics 2 Flashcards

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

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

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)

A

water soluble w/ basic properties

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

22
Q

Streptomycin MOA

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

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

A

inhibits protein synthesis at ribosomal lvl leading to bacteriostasis

25
Q

Tetracyclines info

A
  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
Q

Semi-synthetic tetracyclines

A
  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
Q

Macrolide info

A
  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
Q

2 characteristic sugars of Macrolide?

A

Cladinose and Desosamine

29
Q

Chemical properties of Macrolides

A
  1. chemical instability of earlier ones due to acid-catalyzed internal metal formation resulting in bio-inactivation

Minimized by admin in coated tabs

30
Q

Macrolides MOA

A

Bind to 23S rRNA in polypeptide exit tunnel adjacent to peptides transfer center in 50S ribosomal unit

Peptide formation/elongation step is inhibited

31
Q

Extensive cross resistance between macrolides because….

A

they bind in the same vicinity in 50S ribosomal subunit

32
Q

What mediates bacterial resistance through R-factor enzymes for macrolides?

A

Methylation of specific guanidine residues on their specific ribosomal RNAs to inhibit/reduce macrolide binding

33
Q

Clarithromycin info

A

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
Q

Azithromycin

A

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
Q

Lincosamide MOA

A

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
Q

Chemical properties Lincosamides

A

Weakly basic, salt form w/ acid improve solubility

37
Q

Metabolism Lincosamides

A

extensive liver metabolism resulting primarily in N-demethylation

N-desmethyl analog retains biological activity

38
Q

Lincomycin + Clindamycin are….

A

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
Q

Chloramphenicol info

A

neutral compound poor/mod solubility. improved by forming prodrug

2 chiral centers, 4 stereoisomers possible

givenly orally, rapidly absorbed + short 1/2 life

40
Q

Which stereoisomers of Chloramphenicol are significantly active?

A

1R, 2R

41
Q

Chloramphenicol MOA

A

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
Q

Streptogramins

A

VRSA and VRE usage

synergy observed when using A + B

43
Q

Quinuprisint + Dalfoprisitn

A

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
Q

Linezolid info

A
  1. effective against gram +
  2. Gram - intrinsically resistant due to endogenous efflux pumps
  3. well absorbed orally, comes as tab, iv, suspenison
45
Q

Linezolid MOA

A

binds to 50S sub particle preventing the formation of functional initiation complex

46
Q

Linezolid metabolism

A

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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