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Medicinal Chemistry > Lecture 20, 21, and 22 > Flashcards

Lecture 20, 21, and 22 Flashcards

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1
Q

What is the largest class of beta lactam antibiotics?

A

Cephalosporins

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2
Q

Cephalosporin ring structure is more ___ stable

A

Acid

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3
Q

Are cephalosporins susceptible to acid hydrolysis in the gut?

A

Yes, just not as much as penicillins

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4
Q

How are cephalosporins administered?

A

Many are IV only, but some oral forms also exist

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5
Q

Why are some cephalosporins IV only?

A

Very hydrophilic w/ many H-bond donors and acceptors, and may even be charged; this breaks Lipinski’s rules

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6
Q

Are cephalosporins more or less broad spectrum than penicillins?

A

More broad spectrum

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7
Q

What are cephalosporins effective against that penicillins aren’t?

A

Many gram neg species and more anaerobes

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8
Q

Why are cephalosporins more stable than penicillins?

A

Beta lactam ring strain is much lower

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9
Q

Describe the reactive carbonyl of cephalosporins

A

Like penicillins, the beta lactam carbonyl carbon of cephalosporins is more electrophilic than a typical amine due to lack of resonance

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10
Q

Which area of cephalosporins can be involved in causing beta lactam ring opening?

A

Side chain amide

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11
Q

How can oral absorption of cephalosporins be increased?

A

Using the same strategies to engineer acid resistance in penicillins

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12
Q

Cephalosporins are ___ resistant to beta lactamases than pencillins

A

More (making them broader spectrum)

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13
Q

Which isomer form shoud the oxime group on the R2 (alpha carbon) be in for a cephalosporin?

A

Cis (only this isomer confers beta lactamase resistance; trans isomer has no effect on beta lactamase activity important)

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14
Q

Cephalosporins that cover pseudomonas and MSSA are ___ gen

A

4th

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15
Q

Do cephalosporins cover MRSA?

A

Nope (except a few)

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16
Q

What makes cephalexin orally active?

A
  • EW R2 amino group

- Methyl group on position 3 is hydrophobic, which increases oral absorption but also reduces potency

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17
Q

What is the spectrum of cephalexin?

A
  • Gram pos (strep species, MSSA)
  • Gram neg (E coli, klebsiella)
  • Few anaerobes
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18
Q

What makes cefaclor orally active?

A
  • EW (NH2) R2 group

- Position 3 Cl (increases potency and doesn’t increase hydrophilicity, so has good oral absorption)

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19
Q

What is the spectrum of cefaclor and cefprozil?

A
  • Gram pos (strep species, MSSA)
  • Gram neg (E coli and klebsiella)
  • H. influenza and N. meningitidis
  • Some anaerobes
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20
Q

What makes cefprozil orally active?

A
  • EW R2 group
  • Tyrosine-like group that increases absorption likely by AA transport
  • Position 3 hydrophobic group
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21
Q

What makes cefuroxime axetil more potent than cephalexin? What is a downside to this difference?

A
  • Position 3 group is EW
  • This group is a substrate for esterases (converts inactive form to active form, but also converts active form to a much less active form)
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22
Q

What is the spectrum of cefuroxime axetil?

A
  • Gram pos (strep species, MSSA)
  • Gram neg is broader than cefaclor
  • Some anaerobes
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23
Q

What is cefufroxime axetil used to treat?

A

Non-hospital acquired strep pneumoniae

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24
Q

For cephalosporins, are position 3 groups that are EW and hydrophobic more or less potent compared to EW hydrophilic groups?

A

Hydrophobic = less potent

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25
Q

What is the spectrum of cefixime?

A
  • Gram pos (strep species)
  • Gram neg (E coli, Klebsiella)
  • H. influenza and N. meningitidis
  • Not MSSA
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26
Q

What is cefixime used for?

A

Pediatric UTI’s

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27
Q

What is cefazolin used for?

A

As a surgical antibiotic given 1 hour prior to start and infused during

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28
Q

What makes cefoxitin resistant to beta lactamase?

A

Methoxy group, but this also reduces potency

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29
Q

What is the spectrum of cefoxitin?

A
  • Gram pos (strep species, MSSA)
  • Many gram neg
  • Many anaerobes
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30
Q

What is important to note about the strong EW X group of cefoxitin?

A
  • Potent
  • No oral absorption
  • Susceptible to hydrolysis and spontaneous lactone formation, so shortens t 1/2
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31
Q

What makes ceftriaxone resistant to beta lactamase?

A

Oxime structure

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32
Q

What is the spectrum of ceftriaxone?

A
  • Most gram pos except MRSA
  • Most gram neg
  • Most anaerobes
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33
Q

What is ceftriaxone used to treat?

A

Meningitis

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34
Q

What makes ceftazidime and cefepime resistant to beta lactamase?

A

Bulky oxime structure

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35
Q

What is the spectrum of ceftazidime and cefepime?

A
  • Most gram pos except MRSA
  • Most gram neg
  • Most anaerobes
  • Effective anti-pseudomonal
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36
Q

What is cefepime used to treat?

A

Skin infections, abdominal infections, and pneumonia

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37
Q

What is the spectrum of cefetecol?

A
  • Activity against many gram pos and gram neg

- Anti-pseudomonal

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38
Q

What do all beta lactamase inhibitors have the potential to do?

A

Irreversibly covalently modify beta lactamase

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39
Q

What is the benefit to administering beta lactams w/ beta lactamase inhibitors?

A

Protects beta lactam from hydrolysis by beta lactamase, which widens the spectrum of the beta lactam

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40
Q

How can you make a beta lactam cover MSSA that normally doesn’t cover it?

A

Administer beta lactam w/ beta lactamase inhibitor

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41
Q

What are some beta lactamase inhibitors?

A
  • Clavulanic acid
  • Sulbactam
  • Tazobactam
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42
Q

Which ring structure is the most strained of the beta lactams?

A

Carbapenem

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43
Q

What are characteristics of carbapenems?

A
  • Extremely potent and very broad spectrum
  • Not orally active, IV only
  • Rapidly metabolized (some metabolized by dehydropeptidase 1 in the kidney)
  • Chemically unstable
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44
Q

What makes imipenem susceptible to hydrolysis by dehydropeptidase 1 and how can this be avoided?

A
  • No R2 substitution

- Can be administered in combination w/ cilastatin, which inhibits dehydropeptidase 1

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45
Q

Do carbapenems work against MRSA?

A

Never

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46
Q

What is the spectrum of imipenem and meropenem?

A
  • Most gram pos, except MRSA
  • Most gram neg, even pseudomonas species (so is an anti-pseudomonal)
  • Most anaerobes
  • Meropenem has slightly narrower spectrum, but much higher stability
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47
Q

What is panipenem used in combination w/ and why?

A

Betamipron to inhibit dehydropeptidase 1

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48
Q

What is significant about doripenem?

A
  • Supposedly better anti-pseudomonal than meropenem
  • More chemically stable than imipenem
  • Resistant to dehydropeptidase 1 like meropenem
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49
Q

Which carbapenem is not an anti-pseudomonal?

A

Ertapenem

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50
Q

Why is MRSA resistant to many antibiotics?

A

Has beta lactamase, but main reason is presence of special penicillin binding protein PBP 2a

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51
Q

What does PBP 2a have affinity for?

A

All penicillins, carbapenems, and almost all cephalosporins; these are all the organisms MRSA is resistant to

52
Q

How do antibiotics minimize toxicity to host and maximize toxicity to microorganisms?

A

By targeting metabolic processes that are particular to microorganisms and significantly different from those that happen in human cells

53
Q

Why are most viral infections difficult to treat?

A

Viruses mostly exploit host metabolic processes in order to proliferate

54
Q

What is a plasmid?

A

Circular DNA that can be shared among bacteria and often cary antibiotic-resistant genes

55
Q

Is the protein synthesis machinery of bacterium the same as in humans?

A

No

56
Q

How many of the subunits of a ribosome differ btwn bacterium and humans?

A

Both

57
Q

What is different about the RNA in bacterium compared to humans?

A

In bacteria, there is no 5’ methyl guanine cap, so it is not spliced

58
Q

What is different about transcription btwn bacteria and humans?

A

In bacteria, RNA polymerase and other aspects of transcription are different (no introns and no splicing)

59
Q

Which enzymes involved in DNA synthesis are different btwn bacteria and humans?

A

DNA polymerase, DNA gyrase, and topoisomerase

60
Q

Why do bacteria, yeast, and other single-celled organisms have cell walls?

A

Have high concentrations of osmotically active components (proteins, DNA, RNA, carbs) while environment has low concentrations, so this produces huge osmotic pressure across the cell membrane

61
Q

What do porins do?

A
  • Hydrophilic channel, so some antibiotics can travel through this channel
  • Bacteria w/ less porins = less susceptibility to those antibiotics
62
Q

What are penicillin binding proteins involved in?

A

Peptidoglycan synthesis

63
Q

What is the function of teichoic acids?

A

Increase strength of GM+ cell walls; can be bound to lipid bilayer or peptidoglycan

64
Q

Which 3 characteristics determine what antibiotic therapy should be started?

A

1) Is the bacteria sensitive or resistant to the antibiotic in question? (usually don’t have this info)
2) Is the bacterium GM+ or GM-; could be neither (mycoplasma pneumonia or mycobacterium tuberculosis or leprae)
3) Is the organism anaerobic?

65
Q

What is the most common cause of impetigo?

A

Streptococcus pyogenes, but also Staph aureus

66
Q

What is the most common cause of acute cellulitis?

A

Strep pyogenes

67
Q

What is the most common cause of necrotizing fasciitis?

A

Strep pyogenes

68
Q

What is the most common cause of folliculitis?

A

Staph aureus, sometimes pseudomonas aeruginosa

69
Q

What is the most common cause of furuncles (boils)?

A

Staph aureus

70
Q

What is the most common cause of carbuncle?

A

Staph aureus

71
Q

Which organism is the major cause of hospital acquired infections?

A

Pseudomonas aeruginosa

72
Q

What can pseudomonas aeruginosa cause?

A
  • Pneumonia
  • Sepsis (bacteremia)
  • Skin and soft tissue infection
  • UTI’s
73
Q

Which bacteria have porins?

A

Only GM-

74
Q

Which bacteria have beta-lactamase?

A

GM+ and GM-

75
Q

Which bacteria have penicillin binding proteins?

A

GM+ and GM-

76
Q

Which bacteria have teichoic acids?

A

GM+

77
Q

What makes pseudomonas aeruginosa difficult to treat?

A

Porins channels are difficult to penetrate, and also has fewer porin channels in general

78
Q

What are the most common causes of community-acquired pneumonia?

A
  • Haemophilus influenzae (GM-)
  • Strep pneumoniae (GM+)
  • Moraxella catarrhalis (GM-)
  • Atypical pneumonia caused by mycoplasma pneumoniae (*more common) or legionella pneumophila (most common pneumonia seen in community)
79
Q

What is mycoplasma pneumoniae?

A
  • Parasite of respiratory tract
  • Binds to receptors on tracheal epithelium
  • Extracellular and intracellular pathogen
80
Q

What is NAM attached to in peptidoglycan?

A
  • To unnatural peptide L-Ala-D-Glu-L-Lys-D-Ala

- COOH of NAM connects to peptide via N-alpha amide bond

81
Q

How are adjacent strands of amino sugars attached in peptidoglycan?

A

5x Gly crosslinks adjacent strands via L-Lys and D-Ala (results in L-Lys-Gly-Gly-Gly-Gly-Gly-D-Ala); attached via peptide bonds

82
Q

What is Parks nucleotide?

A

UDP-NAM-L-Ala-D-Glu-L-Lys-D-Ala-D-Ala

83
Q

What is transglycosidation and what catalyzes this process?

A
  • Attaches NAG to NAM

- Catalyzed by transglycosidase

84
Q

What is transpeptidation and what catalyzes this process?

A
  • Connects Gly chain to D-Ala

- Catalyzed by transpeptidase (a penicillin binding protein)

85
Q

What digests amino sugar linages?

A

Lysozyme

86
Q

What is the first step of natural cell wall degradation catalyzed by?

A

Lytic transglycosylases

87
Q

How do penicillins work?

A
  • By covalently binding to penicillin binding protein transpeptidase b/c it “looks” like terminal D-Ala-D-Ala of peptidoglycan
  • Active site Ser reacts w/ the highly strained lactam ring causing the ring to open and form a covalent enzyme intermediate => almost permanent covalent alkylation of transpeptidase enzyme
88
Q

Penicillin is considered a ____ inhibitor of transpeptidase

A

Covalent non-competitive

89
Q

What makes a beta-lactam ring more susceptible to hydrolysis than an amide bond?

A
  • Amide bonds can undergo resonance, which decreases electrophilicity of carbonyl carbon; beta lactam ring can’t undergo resonance
  • S and N help to withdraw electrons from the carbonyl, further increasing the electrophilic nature of the carbonyl
90
Q

What is the cause of MRSA’a resistance to nearly all beta-lactam antibiotics?

A

Penicillin binding protein 2A

91
Q

What are some narrow spectrum beta-lactamase sensitive penicillins and what are they used for?

A
  • Pen G and Pen V

- Used for strep GM+ (except MSSA and MRSA) and some anaerobes (esp. oral anaerobes)

92
Q

What are some narrow spectrum beta-lactamase resistant penicillins and what are they used for?

A
  • Methicillin, nafcillin, cloxacillin, and dicloxacillin

- GM+ staph aurues (MSSA) but not MRSA

93
Q

What are some broad spectrum beta-lactamase sensitive aminopenicillins and what are they used for?

A
  • Ampicillin and amoxicillin

- Many GM+, some GM- (haemophilus influenzae, neisseria meningitidis, E. coli), and some anaerobes

94
Q

What are some broad and extended spectrum beta lactamase sensitive anti-pseudomonals and what are they used for?

A
  • Ticarcillin and piperacillin

- Many GM+ (except MSSA and MRSA), pseudomonas aeruginosa, some anaerobes, and many GM-

95
Q

What does the acid instability of beta lactams cause?

A
  • Basically no oral absorption (other reasons for no oral absorption also)
  • High amounts of penicillin allergies
96
Q

How is the beta lactam ring strain relieved?

A

Opening the ring (acid or base catalyzed; also catalyzed by beta lactamases)

97
Q

What effect does the acyl side chain have on the beta lactam ring?

A
  • Produces a resonance structure that places a negative charge on the side chain carbonyl O, which makes it a better nucleophile
  • The side chain carbonyl O attacks the beta lactam carbonyl, which is particularly reactive => beta lactam ring opening
98
Q

What effect does an EW R group have on a beta lactam antibiotic?

A
  • Decreases attack on the beta lactam carbonyl, producing less ring opening
  • Confers acid stability
99
Q

What is significant about penicillamine?

A

Reactive and involved in penicillin allergy

100
Q

What is significant about penillic acid?

A
  • Can be formed in gut after oral dosing

- Happens readily w/ Pen G and methicillin, but not w/ amoxicillin or Pen V

101
Q

What is significant about penicillenic acid?

A
  • Can be formed easily over a wide pH range
  • Usually always some present in penicillin
  • Very reactive and involved in allergies to penicillin
102
Q

Which compounds promote penicillin allergies that are not anaphylactic?

A

Penicilloic acid and penicillenic acid

103
Q

Why should expired pencillins never be used?

A

Penicilloic acid and penicillenic acid can naturally accumulate in penicillin powder or in liquid formulations, so this promotes the development of penicillin allergies

104
Q

Which compound promotes anaphylactic penicillin allergies?

A

Penicillamine

105
Q

Which penicillins are acid stable? What does this mean?

A
  • Pen V, ampicillin, amoxicillin

- Orally active

106
Q

Do acid resistant penicillins have less incidence of allergy?

A

No

107
Q

Why is amoxicillin used more often than ampicillin?

A

Less side effects

108
Q

What are the 4 methods that bacteria develop resistance to beta lactams?

A
  • Increased production of PBP transpeptidase
  • Mutation of PBP transpeptidase that reduces affinity for penicillin (specifically PBP 2a)
  • Transport of penicillin across outer membrane
  • Production of beta lactamases
109
Q

What do the 4 classes of beta lactamases differ in?

A
  • Structure and mechanism
  • Resistance to inhibitors of beta lactamases
  • Spectrum of activity (types of beta lactams hydrolyzed)
  • Organisms that produce these beta lactamases
110
Q

Where are beta lactamases secreted?

A

Into the medium that the bacteria are growing in, so beta lactams are digested in the medium before they reach the bacterium

111
Q

What is the rate limiting step for beta lactamases?

A

Collision of the enzyme w/ beta lactams

112
Q

What is a part of all beta lactamase resistant penicillins?

A

Aromatic substituent

113
Q

What is the spectrum of cloxacillin?

A
  • Staph aureus (MSSA)
  • Staph epidermidis
  • Strep pyogenes (all GM+)
  • Covers most skin pathogens, so can be used empirically to treat skin infections where MRSA is not suspected
  • No activity against GM-
114
Q

What is the spectrum of amoxicillin?

A
  • GM+ = strep pyogenes, strep pneumoniae, and staph epidermidis
  • Not MSSA or MRSA
  • GM- = E coli, H influenza, N meningitidis, some salmonella, and shigella species
  • Some anaerobes
115
Q

What is a good antibiotic for neonates and children and why?

A
  • Amoxicillin

- Has activity against many of the most common and serious childhood pathogens

116
Q

What makes pseudomonas resistant to beta lactams?

A
  • Low uptake

- Some strains produce beta lactamases

117
Q

How can an antibiotic cross the outer membrane of Pseudomonas aeruginosa and other GM- organisms?

A
  • Through the porin

- Trick an active transporter to take it up into the bacterium

118
Q

How can a beta lactam be modified to pass through the porin of a GM- bacteria?

A

Make the R group very hydrophilic (ex: COOH or ureido group) since the porin is an aqueous channel

119
Q

What do bacteria need from the environment and how do they get it?

A
  • Need iron from the environment
  • Use short peptides call siderophores to chelate iron, and then a special set of active transporters take up the iron-siderophore complex
120
Q

How can an anti-pseudomonal trick an active transporter to take it up into the bacterium?

A

Catechol-substituted cephalosporins have an R group that mimics the catechol structure of siderophores

121
Q

What is ticarcillin and what is it normally given w/ and why?

A
  • Anti-pseudomonal

- Given w/ clavulanic acid b/c it is beta lactamase sensitive

122
Q

What is the activity of ticarcillin?

A
  • Pseudomonas aeruginosa
  • Most GM- and many GM+ (except staph aureus)
  • Many anaerobic bacteria
123
Q

Is ticarcillin or piparcillin more broad spectrum against GM-?

A

Piparcillin

124
Q

All cephalosporins are based on the structure of _____

A

Cephalosporin C

125
Q

How do cephalosporins differ from penicillins w/ respect to activity?

A

Cephalosporins have increase GM- activity and similar GM+ activity, so are more broad spectrum

126
Q

What effect do cephalosporins have on transpeptidase enzymes?

A

Nearly permanently inactivate them

127
Q

What is important about the fact that beta lactams almost permanently covalently modify PBP transpeptidase enzymes?

A

This causes a post-antibiotic effect (there is still activity of penicillins even after 5x their half-life)

Medicinal Chemistry (14 decks)

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