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Anti-Infectives Exam 3 > Lecture 8 - Med Chem Antibiotics 3 > Flashcards

Lecture 8 - Med Chem Antibiotics 3 Flashcards

1
Q

1st gen Quinolones

A

Nalidixic acid = 1st to market, D/c’d
Oxolinic acid
Clinoxacin
Enoxacin

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2
Q

Common structure of quinolone antimicrobials?

A

N-1-alkylated 3-carboxypyrid-4-one ring fused to another aromatic ring

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3
Q

Quinolones absorption

A

well absorbed following oral admin and highly serum protein bound

comparatively long 1/2 life but restricts use mainly to protein free compartments such as urinary track

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4
Q

Presence of what at 6th position improves antimicrobial activity of Quinolones?

A

Fluoro group

inc lipophilicity of molecule which also improves drug pen through bacterial cell walls

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5
Q

Agents containing 6-fluoro referred to as…

A

fluoroquinolones

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6
Q

2nd gen quinolones (fluoroquinolones)

A

Norfloxacin

Ciprofloxacin

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7
Q

Post-antibiotic affect

A

organisms may not resume growth for 2-6hrs after exposure to fluoroquinolone, despite undetectable drug lvls

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8
Q

R6 substitutions help with….

A

cell wall penetration

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9
Q

R7 substitutions help with…

A

spectrum of activity

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10
Q

Essential pharmacophore for activity of 2nd gen quinolones

A

carboxy-4-pyridone nucleus

involved in binding to DNA/DNA gyros enzyme system

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11
Q

SAR 2nd gen quinolones: Reduction of 2,3 double bond or 4 keto group will…

A

inactivate the molecule

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12
Q

SAR 2nd gen quinolones: Substitution at C-2 interferes with…

A

enzyme-substrate complexation due to steric hinderance

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13
Q

C6 fluro group on 2nd gen will…

A

increase DNA/gyrase/topoisomerase IV inhibitory action

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14
Q

what group at N-1 will broaden antimicrobial activity of quinolones

A

Cyclopropyl

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15
Q

Quinolones MOA

A

Bactericidal action results from inhibition of DNA gyrase and topoisomerase IV

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16
Q

Why dont quinolones kill host cells?

A

Humans use Topoisomerase II, this doesn’t bind to quinolones

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17
Q

Chemical incompatibilities of quinolones

A

chelate metal ions and lose potency

dont give with Ca, Mg, Al supps or dairy

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18
Q

3rd/4th gen quinolones

A

3rd gen = gatifloxacin + gemifloxacin

4th gen = moxifloxacin + trovafloxacin

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19
Q

Sulfonamides MOA

A

Antimicrobial activity by interfering with folate synthesis

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20
Q

Step by step MOA Sulfonamides

A
  1. Bacteria use PABA to make folic acid
  2. purees essential for DNA synthesis
  3. Sulfonamides similar to PABA, but have higher afifinity for dihydropteroate synthase
  4. sulfonamide will bind instead of PABA, leading to inhibition of DNA synthesis
21
Q

Sulfisoxazole info

A
  1. one of most popular sulfonamide w/ broad antimicrobial spectrum in vitro
  2. clinically use restricted ti uncomplicated UTI
22
Q

Sulfisoxazole structural features

A
  1. Acidity of N attached to aromatic SO2 grp is inc by attaching EW ring
  2. this inc acidity inc antibacterial potency but also dramatically inc water solubility under physiologic conditions
  3. this addresses problem of insolubility leading to crystallization in urine associated with earlier sulfonamides
23
Q

Sulfonamide resistance

A
  1. Common and involves alterations in Dihydropteroate synthase*** so that is discriminates better between PABA and sulfonamides
  2. Bacteria able to take up preformed folic acid into cells are intrinsically resistant to sulfonamides
24
Q

Sulfsalazine info

A
  1. treat UC and CD
  2. pro drug, missing free para-amino = inactive antibacterial
  3. its red ago dye given orally, not absorbed in gut and majority delivered to distal bowel
  4. Reductive metabolism by gut bacteria convert to sulfapyridine and 5-ASA (mesalamine) = purpose for admin of drug
25
Q

Trimethoprim works by…

A

inhibition of action of dihydrofolate reducatase

Bacterostatic mainly used in prophylaxis and treatment of UTI

26
Q

Trimethoprim selectivity between bacterial and mammalian dihydrofolate reductase results from…

A

subtle but significant architectural difference between the two enzymes

27
Q

Metronidazole

A

Flagyl, antibiotic + antiprotozoal

comes in oral, cream or IV

28
Q

Metronidazole MOA

A

Nitroimidazole class

inhibits nucleic acid synthesis by disrupting the DNA of microbial cells

only occurs in anaerobic cells

29
Q

Isoniazid for TB

A

acts as bactericidal by affecting the synthesis of lipids, NA and Mycelia acid of cell wall of these species

30
Q

Isoniazid MOA

A

Bio activation of INH

  1. INH = prodrug, activated by oxidation via KatG to reactive species capable of acylating enzyme system found exclusively in M.Tuberculosis
  2. mycelia acid important part of mycobacterial cell well. inhaler important enzyme
  3. activating intermediates from INH interact with NADH bound within active site of inhaled to form acylated NDA which is no longer capable of catalyzing reduction of unsaturated fatty acids which are essential for synthesis of mycloic acids.
31
Q

INH resistance

A

loss of catalyst activity is associated with the deletion of catalase gene, katG as well as over expression of of InhA

32
Q

INH metabolism

A
  1. readily absorbed from GI
  2. extensively metabolized to inactive metabolites
  3. Acetylhydrazine serves as CYP450 substrate resulting in formation of reactive intermediate which capable of acylating liver protein resulting in liver necrosis **
33
Q

Major metabolite INH

A

N-acetylisoniazid, formed by action of N-acetyltransferase

34
Q

Which metabolite of INH plays role in liver necrosis?

A

Acetylhydrazide

35
Q

Rifamycin Antibiotic MOA

A

inhibit bacterial DNA-dependent RNA polymerase by strongly binding to B-subunit of enzyme.

Inhibition of DDRP leads to blocking of initiation of chain formation in RNA synthesis

** No effect once polymerization has begun ***

36
Q

Benefit of Rifampin + Rifapentine

A

Significant benefit over prev investigated rifamcyins in that they’re orally active, highly effective, and high clinical efficacy in oral txm of TB

37
Q

Detailed MOA Rifamycin

A
  1. suggested that naphthalene ring of rifamycins pi-pi bonds to an aromatic amino acid ring in DDRP protein
  2. DDRP metalloenzyme which contains 2 zinc atoms
  3. C1/C8 of rifamycin chelate to zinc atom, inc binding to DDRP and O at C21/C23 form strong H bond to DDRP
  4. binding to DDRP results in inhibition of RNA synthesis
38
Q

SAR Rifamycin

A
  1. Free OH groups req at C1/C8/C21/C23 + appear to lie in plane
  2. Acetylation at C21/C23 = inactive compounds
  3. reduction of double bond in ring results in dec activity
  4. opening macro ring = inactive compound
39
Q

Pyrazinamide info

A
  1. bioisostere of nicotinamide, possess bactericidal action
  2. activity is pH depending w// good in vivo activity at pH 5.5 but nearly inactive at neutral pH***
  3. especially beneficial active against semi dormant intracellular tubercle bacilli that are not affected by other drugs.
40
Q

Pyrazinamide MOA

A
  1. prodrug, converted into active form Pyrazinoic acid (POA) by bacterial nicotinamidase/pyrazinamidase (PZase)
41
Q

Pyrazinamide Metabolism

A
  1. readily absorbed after oral admin, little excreted unchanged
  2. major metabolic route consists of hydrolysis by PZase to pyrazinoic acid then oxidized by Xanthine oxidase to 5-hydropyrazinoic acid
42
Q

Ethambutol info

A

1.Bacterostatic for TB

+ enantiomer is 200-500X moe active than - enantiomer

usually given in combo w/ other TB drugs

43
Q

Ethambutol MOA

A
  1. not completely known
  2. exerts bacteriostatic activity by inhibition of arabunosyl transferase, an enzyme that polymerizes arbinose into Arabian and then arabinogalactan, a mycobacterial cell wall constituent
44
Q

Ethambutol mechanism of resistance

A

involves gene over expression of arabinosyl transferase

45
Q

Ethambutol Metabolsim

A
  1. majority oral admin excreted unchanged, no more than 15% appear as Metabolite A/B
  2. both metabolites are devoid of biologic activity
46
Q

Cell wall/cell envelope of mycobacterium

A
  1. Plasma membrane
  2. Peptidoglycan layer
  3. AG
  4. Layer of mycolylates
  5. LAM
47
Q

Second line TB agents

A 
Ethionamide
Para-aminosalicyclic acid
cycloserine
capreomycin
kanamycin

usually less well tolerated or higher incidence of ADE

usually used in case of resistance

48
Q

Ethionamide info

A
  1. Bactericidal
  2. MOA: similar to INH, prodrug converted to active acylating agent, which inactivates inhaled
  3. orally active, but single large dose (>500mg) not well tolerated. SE = GI,CNS, sensitivity
49
Q

PAra-Aminosalicylic Acid (PAS)

A

used as 2nd line due to resistance and SE

thought to act as antimetabolite interfering with in crop of para-amino benzoic acid into folic acid

When co-admin w/ INH found to reduce acetylation of INH, thus increasing plasma lvls of INH

Anti-Infectives Exam 3 (7 decks)

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