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Anti-Infectives Exam 3 > Lecture 6 - Med Chem Antibiotics 1 > Flashcards

Lecture 6 - Med Chem Antibiotics 1 Flashcards

1
Q

Antimicrobial agents are….

A

synthetic substances that are unrelated to natural products but still inhibit or kill microorganisms

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2
Q

Broad Spectrum activity is….

A

wide range of bacteria

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3
Q

Narrow Spectrum activity is…

A

limited subset of bacteria

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4
Q

Bacteriostatic is…

A

stop bacteria from multiplying

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5
Q

Bactericidal will….

A

kill bacteria

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6
Q

Antibiotics are….

A

microbial metabolites or synthetic analogs inspired by them that, in small doses, inhibit the growth and survival of microorganisms without serious toxicity to the host.

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7
Q

Beta Lactam Antibiotics….

A 
Penicillins
Cephalosporins (1-4th gen)
Carbapenems ( imipenem + meropenem)
Monobactam ( aztreonvam)
Glycopeptides (vancomycin + teicoplanin)
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8
Q

Penicillin….

A

natural penicillins
Anti-staphylococcal
Aminopenicillins
Anti-pseudomonas penicillins

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9
Q

Gram (-) bacterial membrane structure

A

2 membranes

Out membrane functions as efficient permeability barrier containing LPS + Porins

Peptidoglycan (murrain) polymer consisting of sugar + amino acids that forms mesh-like layer outside the plasma membrane

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10
Q

PBP

A

Penicillin Binding Protein

Site of Penicillin Action

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11
Q

Gram (+) bacterial membrane structure

A

simpler than that of Gram (-)

lipid billayer cell membrane of most + bacteria is covered by a porous peptidoglycan layer

Beta-lactamases are secreted outside the gram + cell and must be replenished frequently

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12
Q

Lactam =

A

Cyclic amide

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13
Q

B- Lactam =

A

Cyclic amide w/ 4 atoms in its ring

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14
Q

Penam =

A

4 atom cyclic amide
S at 4
no double bond 2-3

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15
Q

Penem

A

4 atom cyclic amide
S at 4
double bond 2-3

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16
Q

Carbapenem

A

4 atom cyclic amide
No S in other ring
Double bond 2-3

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17
Q

Cefam

A

4 atom cyclic amide
S is at 5**
Double bond at 2-3

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18
Q

Monobactam

A

4 atom cyclic amide

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19
Q

Beta-lactam info

A

called beta- because cyclic addition occurs between b position and NH

have strain, generally not stable, water will hydrolyze

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20
Q

Why don’t you want to store beta-lactams in metal container?

A

easily hydrolyzed by water or other metal ions

store in glass or plastic

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21
Q

Fermentation-Derived Penicillins

A

Original Fermentation derived penicillin were produced by Penicillium chrysogenum

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22
Q

During fermentation, if sufficient supply of phenyl acetic acid you produce mainly….

A

Benzylpenicillin

Penicillin G

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23
Q

During fermentation, if sufficient supply of Phenoxyacetic acid you produce mainly…

A

Phenoxymethylpenicillin

Penicillin V

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24
Q

during fermentation, exclusion of side chain precursor acids leads to production of….

A

6-APA
6-aminopenicillinic acid

** Has very weak antibiotic activity **

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25
Q

6-aminopenicillinic acid. has addition of what at C6 of Penam…..

A

H2N, nothing extra

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26
Q

Penicillin V has addition of what at C6 of Penam….

A

H2N, connected double bond O - C - 6 C ring with double bonds

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27
Q

Clinically relevant degradation reactions of Penicillins?

A
  1. most unstable bond in the penicillin molecule is the highly strained and reactive B-lactam amide bond
  2. Slow cleavage in water unless heated; rapid cleavage in acidic and basic media
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28
Q

What controls the nature of Hydrolysis of Penicillins?

A

The nature of R group added to N2H off of C6

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29
Q

Penicillin G has addition of what at C6 of Penam….

A

H2N, connected to double bond O, C - O - 6 C ring with double bonds

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30
Q

Why do penicillins bind to PBPs?

A

Beta-lactam resembles the amnio acid it needs to build ALA structure, by mistake it takes up Beta-lactams which will cause the PBP to lock and it won’t be able to construct the way.

Need to protect B-lactam bond from acid so that it still retains this activity

Beta-lactamases are what chops this bond

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31
Q

how to protect penicillins in part from acid degradation?

A

adding side chain R group (Benzyl or phenoxymethyl) which is EWG, decrease electron density on the side chain carbonyl

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32
Q

Oral survival of Benzylpenicillin (G) vs phenoxymethyl penicillin (V)

A 
G = 15-30% survives
V = 60-73% survives
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33
Q

As lipophilicity of side chain of penicillin increases, serum protein binding of antibiotic will…

A

increase

This leads to partial protection from degradation but it does not reduce effective bactericidal conc of the drug

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34
Q

degree of serum protein binding of penicillins has how much influence upon their half-lines?

A

little

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35
Q

Penicillins + Beta-lactam MOA

A
  1. Closely resemble geometry of acylated D-ala-D-ala (cell wall segment)
  2. PBP mistakenly accepts it as a normal substrate
  3. This leads to selective and irreversible inhibition of PBP enzyme
  4. This result in structurally weak cell wall, subject to osmotic stress. Cell lysis can result and cell rapidly dies
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36
Q

EDG vs EWG R group on hydrolysis

A 
EDG= More hydrolysis
EWG = Slower Hydrolysis
37
Q

B-lactamases are…

A

enzymes (serine proteases) elaborated by microorganisms that catalyze hydrolysis of the b-lactam bond and inactive b-lactam antibiotics to penicillin acids before they can reach PBPs

38
Q

What allows B-lactamases to turn over many times and allows for a comparatively small amount of enzyme to destroy a large amount of drug?

A

Hyrdolytic regenerations of the active site are more facile than with the cell wall transamidase

39
Q

B-lactamases in Gram +

A

ie Staphylococci

B-lactamases are shed continuously into the medium and meet the drug outside the cell wall

40
Q

B-lactamases in Gram -

A

Secreted into periplasmic space between inner/outer membrane, they dont readily escape into medium and need no be resynthasized

41
Q

How do drugs try to reduce being attacked by B-lactamases?

A

By creating steric hinderance protecting the bond that B-lactamases attacks

42
Q

Semi-synthetic Penicillins

A

Structural modifications made to the side chain of penicillin nucleus in an effort to improve oral bioavailability, improve stability to B-lactamase activity, and inc spectrum of action

43
Q

Anti-staphylococcal (Penicillinase-Resistant) Penicillins

A

Methicillin ( 2 OMe)
Nafcillin

Resistance to enzyme degradation based on steric hinderance

OMe group is EWG by inductive, EDG by resonance. resonance donating effect is stronger

44
Q

Why is Methicillin unstable to gastric acid?

A

Due to donating effect of OMe

45
Q

Methicillin vs nafcillin resistance to B-lactamase?

A

Nacficllin&raquo_space; due to more bulk/steric hinderance

46
Q

Narrow Spectrum Penicillinase-Resistant Oral Penicillins due to

A
  1. Resistance to enzyme degradation based on steric hindrance and stability to acid hydrolysis through chemical modification
  2. Replacement of phenyl ring with isometric isoxazolyl ring substituted with methyl and phenyl groups
47
Q

Isoxazolyl ring is….

A

electrons withdrawing, leads to improved stability of lactase ring to acid hydrolysis

48
Q

Narrow Spectrum Penicillinase-Resistant Oral penicillins examples

A

Oxacillin
Dicloxacillin = 2 Cl groups on ring
Flucloxacillin

-Cloxacillin = only 1 chloro group on ring

49
Q

Cloxacillin vs Dicloxacillin oral bioavailability and renal elim

A

Cloxacillin = 36.9% bioavailability, 33min renal elim

Dicloxacillin = 48.8% bioavailability, 42min renal elim

More Cl = more lipophilic = inc half life

50
Q

Broad Spectrum Penicillinase-Sensitive Oral Penicillins

A

Aminopenicillins

51
Q

Aminopenicillins info

A
  1. replace H of side chain ethylene w/ primary amino group
  2. EW amino group in protonated form improves stability of lactam ring towards acid hydrolysis = makes orally active
  3. Broad spectrum, sensitivity to (-) due to greater pen of ampicillin into gram (-) bacteria)
52
Q

Aminopenicillins lack…..

A

stability towards B-lactamases, add Clavulanic acid (a mold product) which has weak antibacterial activity but has excellent irreversible inhibition of most b-lactamases

** can also add sulbactam, oxidation of sulphur atom to sulfone greatly enhances potency of sulbactam ***

53
Q

Speculative Mechanism for irreversible inactivation of B-lactamases by clavulanic acid and sulbactam

A

b-lactamase will attack Clavulanic acid or Sulbactam and it will bind forming a complex and gets stuck

54
Q

Enhancement of Ampicillin’s Oral Bioavalibility through prodrug formation

A

Ampicillin well absorbed, oral efficacy for systemic infection can be enhanced through prep of prodrug

Bacampicillin = weak base, rapidly/well absorbed in duodenum and quickly cleaved by serum esterase’s to bioactive ampicillin

55
Q

Penicillinase-sensitive, broad-spectrum, parenteral penicillins

A

Piperacillin
Azlocillin
Mezlocillin

Also known as Acylureidopenicillins

56
Q

Acylureidopenicillins info

A

preserve Gram + activity, but have higher Gram - potency

oral stability gone because -NH2 group no more basic after structural modifications

57
Q

Ticarcillin info

A

A carboxypenicllin and used in combo w/ clavulanate a Timentin

Not well absorbed orally, given IV or IM

58
Q

Cephalosporin info

A
  1. 1st isolated from cultures of Cephalosporium acremonium from sewer in Sardinia in 1948
  2. Degradation of side chan by chemical means produces 7-ACA
  3. Modification of 7-ACA side chain resulted in development of useful antibiotic agents
  4. Allergenicity is less commonly experienced and is less severe with cephalosporins than with penicillins
59
Q

Cephalosporins vs penicillin structure

A

cephalosporins have b-lactam ring attached to 6 member ring, penicillins have attached to 5 member ring

this makes them less strained and less reactive/potent

60
Q

What makes up reactivity loss in Cephalosporins?

A
  1. possession of olefinic linkage at C-2,3
  2. methyleneacetoxy group at C3

this reduces energy required for b-lactam ring to be opened by hydrolysis

61
Q

What modulates the facility with which the B-lactam bond of the Cephalosporins is broken?

A

nature of C-7 substituent

nature of C-3 substituting + its ability to carry away neg charge

62
Q

Cephalosporin MOA

A

bacterial and have the same mode of action as other b-lactam antibiotics such as penicillins

63
Q

Cephalosporin Metabolism

A

Active -> (esterase) = much less active -> (spontaneous lactonization) = Inactive

64
Q

1st gen Cephalosporins

A

good activity against + but less against -

most + cocci are susceptible (not including enterococci + MR staph)

65
Q

Oral 1st gen

A

Cephalexin
Cefadroxil
Cephalothin

66
Q

Parenteral 1st gen

A

Cephazolin

Cephradine

67
Q

Cephradine

A

Interesting drug design, Partial hydrogenation (Bird reduction) of the aromatic ring - No conjugated olefinic

Comparatively acid stable and hence rapidly and near completely absorbed from GI

Can be used both orally and IM

68
Q

How to tell if 1st gen cephalosporin will have metabolic inactivation

A
  • CH3 off C3 = no, maintain potency

- Ester off C3 = yes

69
Q

2nd gen cephalosporin agents

A

grater - activity while retaining gram + cocci activiy

more resistant to beta-lactamase

70
Q

Oral 2nd gen

A

Cefaclor

Cefuroxime xetil

71
Q

Parenteral 2nd gen

A

Cefamandole ( improve activity against H. influenzae)
Cefonicid ( long 1/2 life)
Cefuroxime
Cefoxitin ( anaerobic coverage for B. fragilis)

72
Q

How does 2nd gen bring stability to B-lactamases?

A

Target C7 ( OMe = steric hinderance) or C3 sites (Cl = EWG = helping with opening but not good leading group)

73
Q

3rd gen cephalosporin agents

A

broad spectrum of activity and further inc activity against gram -

those in oral form + those w/ anti-pseudomonas activity have decreased activity against gram + organisms

74
Q

Oral 3rd gen

A

Ceftibuten

75
Q

Parenteral 3rd gen

A

Cefotaxime ( Good gram +, excellent CNS pen)
Cefoperazone (antipseudomonal, dec gram +)
Ceftazidime (antipseudomonal, dec gram +)
Ceftriaxone (long T1/2, excellent CNS pen)

76
Q

Syn- vs Anti- configuration for activity in 3rd gen cephalosporins

A

Syn = better hinderance, closer to amide

better b-lactam stability

77
Q

4th gen Cephalosporins

A

extended spectrum agents w/ similar gram + activity as 1st gen

greater resistance to beta-lactamases than 3rd gens

can cross BBB ( CSF ~ 10%) and are effective in meningitis

Also used against Pseudomonas aeruginosa and post operative intracranial infection

78
Q

4th gen cepahlosporin is…

A

Cefepime

79
Q

Modification of cefepime

A

N-Methylpyrrolidine group at C3

increases penetration into gram - bacteria

80
Q

Carbapenems

A
  1. kill bacteria by bing to PBP and inhibit cell wall synthesis
  2. exhibit broad spectrum of activity compared to cephalosporins + penicillin, effectiveness less affected by B-lactam resistance
  3. sulfor atom not part of 5-member ring but replaced with methylene at that position
  4. Sulfor atom attached at C3 as part of functionalized side chain. Endocylcic olefinic linkage enhances reactivity of B-lactam ring
81
Q

1st carbapenem isolated

A

thienamycin, from Streptomycin Cattleya

unstable in aqueous solution so impractical to admin to patients.

self inactivating due to primary -NH2

82
Q

Imipenem basic info + how it was made

A

IV not Oral

terminal amino group at C3 attacks b-lactam bond of nearby molecule and destroy activity

problem solved by changing amino to less nucleophilic N-formiminoyl moiety to make Imipenem ***

83
Q

Imipenem info

A

penetrates well through porins and very stable, even inhibitory to many B-lactamases

Not orally bioactive

given w/ Cilastatin to protect it from Renal Dehydropeptidase which hydrolyses it through B-lactam bond

84
Q

Meropenem info

A

Addition of chiral methyl group at C4 = intrinsic resistance to hydrolysis by dehydropeptidase-1 so it can be admin alone

common SE similar to imipenem/cilastatin but less serious

85
Q

Aztreonam info

A

totally synthetic parenteral antibiotic whose antimicrobial spectrum is devoted almost exclusively to gram - microorganism and is capable of inactivating some b lactamases

similar MOA to penicillins, etc

sulfuric acid moiety strong EWG, makes bond more susceptible to hydrolysis

86
Q

Glycopeptide Antibiotics info

A
  1. inhibit cell wall synthesis by inhibiting peptidoglycan synthesis
  2. bind to acyl-D-alanyl-D-alanine in peptidoglycan

effective primary against gram + cocci

87
Q

Vancomycin info

A

large, hydrophilic

not absorbed from intestine, poor oral bioavailability

must be given IV for systemic therapy

88
Q

Teicoplanin

A

Semisynthetic glycopeptide, similar spectrum of activity to Vanco

treatment of serious infections by Gram +, MRSA

mixture of several compounds

50X-100X more lipophilic than vancomycin

increased 1/2 life, better tissue pen

2-4x more active than vanco

more acidic, so can be given IV

Anti-Infectives Exam 3 (7 decks)

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