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CH 456 Medicinal Chemistry > Chapter 19 Antibacterial Agents > Flashcards

Chapter 19 Antibacterial Agents Flashcards

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1
Q

True or False: Bacterial infections are major worldwide health risk and difficult to treat due to development of resistance

A

Tfue

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2
Q

True or False: Antibiotics come from natural products

A

True

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3
Q

In order for _____ to have proper treatment often requires identification of bacteria including testing for antibiotic sensitivity

A

Antibiotics

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4
Q

ancient ______ applied mouldy bread to infected wounds

A

Egyptians

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5
Q

______ reported the antibacterial power of some extracts of mould

A

Vincenzo Tiberio 1895

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6
Q

_______ discovered ______ was an effective treatment for syphilis “principle of chemotherapy” – a chemical could inhibit micro-organism proliferation at concentrations tolerated by the host

A

Paul Ehrlich 1909 arsphenamine

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7
Q

______ led to sulphonamides, the first effective antibacterial agents

A

Prontosil 1935

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8
Q

Penicillin 1942 identified by ______ in 1928 but not purified until 1942

A

Alexander Fleming

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9
Q

The cell wall of ______ bacteria consists of a thin layer of peptidoglycan while______ bacteria have a single lipid membrane surrounded by a cell wall composed of a thick layer of peptidoglycan

A

Gram-negative Gram-positive

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10
Q

Cell walls of ______ consist of thin layers of peptidoglycan and arabinogalactan, and a thick layer of mycolic acids33. Glycolipids and porins are also found in these cell walls, as is lipoarabinomannan, which is anchored to the cell membrane by diacylglycerol. This cell wall surrounds a single lipid membrane

A

mycobacteria

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11
Q

A single plasma membrane is also present in ______, surrounded by a cell wall consisting of various layers of the polysaccharides chitin, β-glucan and mannan (in the form of mannoproteins).

A

fungi

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12
Q

What are the 5 mechanisms of antibacterial action?

A

Inhibition of cell metabolism Inhibition of bacterial cell wall synthesis Interactions with the plasma membrane Disruption of protein synthesis Inhibition of nucleic acid transcription and replication

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13
Q

______ antibiotics inhibit microorganism metabolism, but not the metabolism of the host

A

Inhibition of cell metabolism sulphonamides

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14
Q

______ antibiotics leads to bacterial cell lysis and death

A

Inhibition of bacterial cell wall synthesis penicillins, cephalosporins, glycopeptides such as vancomycin

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15
Q

______ antibiotics interact with the bacterial plasma membrane to affect permeability

A

Interactions with the plasma membrane polymyxins, tyrothricin

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16
Q

______ antibiotics effect essential proteins and enzymes can no longer be made

A

Disruption of protein synthesis rifamycins, aminoglycosides, tetracyclines, chloramphenicol

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17
Q

______ antibiotics prevents cell division and/or the synthesis of essential proteins

A

Inhibition of nucleic acid transcription and replication nalidixic acid, proflavine

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18
Q

There are approximately ____ conserved essential proteins in bacteria, but the number of currently exploited targets is very small.

A

200

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19
Q

The most successful antibiotics hit only three targets or pathways, what are they?

A

the ribosome (which consists of 50S and 30S subunits) cell wall synthesis DNA gyrase or DNA topoisomerase

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20
Q

____ is a fluoroquinolone antibiotic that targets DNA gyrase and DNA topoisomerase

A

Ciprofloxacin

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21
Q

____ is a semi-synthetic β-lactam that inhibits cell wall synthesis and targets several penicillin-binding proteins

A

Ampicillin

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22
Q

______ is a aminoglycoside that is a inhibitor of protein synthesis and targets 16S ribosomal RNA

A

Streptomycin

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23
Q

in 1935 when _____ was discovered that a red dye called prontosil had antibacterial properties in vivo but not in vitro (i.e., a prodrug)

A

Sulphonamides

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24
Q

Sulphonamides have antimetabolites that inhibit competitively bacterial ______.

A

dihydropteroate synthetase (DHPS) DHPS plays a role in the synthesis of tetrahydrofolate (THF), an intermediate in the synthesis of thymidine

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25
Q

True or False: Sulphonamides are bacteriocidal

A

False, bacteriostatic

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26
Q

_______ is the most widely prescribed sulphonamide today

A

sulphamethoxazole sulphamethoxazole and trimethoprim (inhibits dihydrofolate reductase (DHFR), are often co-formulated and administered together *known as sequential blocking

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27
Q

True or False: Sulphonamides and trimethoprim both inhibit synthesis of tetrahydrofolate

A

True

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28
Q

How are sulfonamides competitive enzyme inhibitors

A

Sulphonamide prevents PABA from binding by mimicking PABA.

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29
Q

The _______ or the______ involves the design of chemicals which show selective toxicity against bacterial cells rather than mammalian cells.

A

principle of chemotherapy magic bullet

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30
Q

Early antibacterial agents were _____, ______, and _______.

A

salvarsan, prontosil, and the sulphonamides

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31
Q

Following the discovery of penicillin, several classes of antibiotics were isolated from _______.

A

fungal strains.

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32
Q

______require a primary aromatic amine group and a secondary sulphonamide group for good activity.

A

Sulphonamides

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33
Q

True or False: Adding an aromatic or heteroaromatic group to the sulphonamide nitrogen provides a variety of sulphonamides with different pharmacokinetic properties.

A

True

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34
Q

______ of sulphonamides is a common metabolic reaction.

A

N-Acetylation

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35
Q

Sulphonamides are used to treat infections of the_____, ______ and _______.

A

urinary tract, gastrointestinal tract, and mucous membranes.

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36
Q

______ synthesize tetrahydrofolate from folic acid acquired from the diet. They lack the enzyme targeted by sulphonamides. _____ lack the transport mechanisms required to transport folic acid into their cells.

A

Mammals Bacteria

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37
Q

Sulphones are used in the treatment of ______.

A

leprosy

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38
Q

______ inhibit cell wall synthesis and is characterized by an amide in a four-membered ring while the _____ functional group reacts irreversibly with transpeptidase enzyme in bacteria to stop cell wall synthesis

A

β-lactam

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39
Q

______ contain a β-lactam fused to a 5-membered thiazolidine ring with a sulphur atom

A

Penicillin penicillin V normally as its potassium salt

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40
Q

What are the 4 components of penicillin structure?

A

Acyl side chain β-lactam ring Thiazolidine ring 6-APA

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41
Q

Penicillin inhibits cross-linking of bacterial cell walls by irreversibly reacting with the enzyme _______

A

transpeptidase

42
Q

penicillin G is acid-sensitive so it can not be administered what way?

A

Orally

43
Q

Why is it hard to counteract acid sensitivity?

A

cannot alter ring strain or the highly reactive β-lactam carbonyl group

44
Q

How do you counteract acid sensitivity?

A

achieved by reducing the amount of neighbouring group participation an electron-withdrawing group was placed in the side chain that could draw electrons away from the carbonyl oxygen and reduce its tendency to act as a nucleophile

45
Q

______ has an electronegative oxygen on the acyl side chain with the electron withdrawing effect required and has better acid stability than penicillin G and is stable enough to survive the acid in the stomach, so it can be given orally

A

Phenoxymethylpenicillin (penicillin V)

46
Q

What are the 5 resistance mechanisms to penicillins?

A

physical barriers

β-lactamases that hydrolyze the β-lactam ring

high levels of transpeptidase enzyme

mutations that alter the affinity of transpeptidase for penicillins

transport back across the outer membrane of Gram-negative bacteria

47
Q

What are two examples of physical barriers that cause penicillin resistance?

A

Gram-negative bacteria have an outer lipopolysaccharide membrane which is impervious to polar molecules like penicillin porins in outer membrane of some Gram-negative bacterial strains allow penicillins to be effective

48
Q

The use of ______ to block penicillin from reaching the β-lactamase active site enzymes.

A

steric shields (bulky group)

49
Q

_____ and ______ have a positively charged amino group that enhances their uptake through bacterial porin channels

A

ampicillin and amoxicillin

50
Q

True or False: both ampicillin and amoxicillin compounds are acid resistant

A

True, because of the presence of the electron-withdrawing amino group so can be given orally

51
Q

True or False: both ampicillin and amoxicillin have steric shields

A

False, therefore they are sensitive to β‑lactamase enzymes

52
Q

_____ was the first carboxypenicillin

A

carbenicillin

53
Q

Why is there a broad spectrum of carboxypenicillins?

A

due to the hydrophilic carboxylic acid group

54
Q

_____ and ______ are prodrugs for carbenicillin and show an improved absorption through the gut wall

A

carfecillin and indanyl carbenicillin

55
Q

ticarcillin is similar carbenicillin, but has a ______ ring

A

thiophene

56
Q

Penicillins have a ______ structure consisting of a β-lactam ring fused to a thiazolidine ring

A

bicyclic structure

57
Q

Penicillin analogues can be prepared by ______ or by a ________

A

fermentation semi-synthetic synthesis from 6-aminopenicillanic acid.

58
Q

Variation of the penicillin structure is limited to the _______.

A

acyl side chain

59
Q

True or False: Penicillins can be made more resistant to acid conditions by incorporating an electron-withdrawing group into the acyl side chain.

A

True

60
Q

_____ activity is associated with the presence of an α‑hydrophilic group on the acyl side chain of penicillin.

A

Broad spectrum

61
Q

_______ are the second major group of β-lactam antibiotics discovered and its β-lactam ring is fused with a 6-membered ring with a sulphur atom

A

Cephalosporins

62
Q

_____ was the first cephalosporin discovered isolated from fungus found in sewer waters in Sardinia

A

Cephalosporin C

63
Q

True or False: Cephalosporin C has 1/1000 of activity of penicillin G but has broader spectrum of activity and is less susceptible to acid hydrolysis and β-lactamases

A

True therefore viewed as useful lead compound for development of more potent broad spectrum antibiotics

64
Q

What are the 4 parts of the cephalosporins ?

A

Aminoadipic side chain B-lactam ring Dihydrothiazane ring 7-ACA

65
Q

What is the mechanism by which cephalosporins inhibit the transpeptidase enzyme?

A

Through aminoadipic side chain

66
Q

_______ in general, they have a lower activity than comparable penicillins, but a better range of activity and most have poor oral bioavailability and have to be injected

A

First-generation cephalosporins e.g., cephalothin, cephaloridine, cephalexin, cefazolin

67
Q

What are the 3 types of second generation cephalosporins?

A

cephamycins cefoxitin oximinocephalosporins

68
Q

______contain an advantageous methoxy substituent at position 7

A

cephamycins

69
Q

True or False: unlike most cephalosporins, cephamycins are effective against anaerobic microbes

A

True

70
Q

parent compound ____ was isolated Streptomyces clavuligerus

A

cephamycin C the first β-lactam to be isolated from a bacterial source (stabilizes neighbouring carbonyl group)

71
Q

_____ has broader spectrum of activity than most first-generation cephalosporins due to greater resistance to β-lactamase enzymes

A

cefoxitin may be due to the steric hindrance provided by the methoxy group

72
Q

_____ provided major advance in cephalosporin research and contain an iminomethoxy group at the α-position of the acyl side chain

A

oximinocephalosporins significantly increases the stability of cephalosporins against the β-lactamases produced by some organisms (e.g., Haemophilus influenza ) the first useful agent in this class of compounds was cefuroxime

73
Q

______ cephalosporins are modified oximinocephalosporins

A

Third-generation replacing furan ring with an aminothiazole ring

74
Q

In third generation cephlapsorins, by replacing the furan ring with an aminothiazole ring what happens?

A

enhances the penetration of cephalosporins through the outer membrane of Gram-negative bacteria and may also increase affinity for the transpeptidase enzyme variety of substituents at position 3 to vary the pharmacokinetic properties e.g., ceftazidime, cefotaxime, ceftizoxime, ceftriaxone

75
Q

_____ and _____ are fourth generation cephalosporins

A

cefepime and cefpirome

76
Q

oximinocephalosporins (4th generation) that are ______ compounds having a positively charged substituent at position 3 and a negatively charged carboxylate group at position 4

A

zwitterionic *this appears to radically enhance the ability of these compounds to penetrate the outer membrane of Gram-negative bacteria

77
Q

True or False: fourth generation cephalosporins also have a good affinity for the transpeptidase enzyme and a low affinity for a variety of β-lactamases.

A

True

78
Q

______ cephalosporins has activity against various strains of MRSA and multidrug-resistant Streptococcus pneumonia (MDRSP) and acts as a prodrug for ceftaroline

A

Fifth-generation, ceftaroline fosamil

79
Q

In fifth-generation cephalosporins, the ______ is thought to be important for its activity against MRSA

A

1,3-thiazole ring

80
Q

Know this chart

A
81
Q

¢Variation of the ______ side chain alters antimicrobial activity, whereas variation of the side chain at ______ predominantly alters the metabolic and pharmacokinetic properties of the compound. Introduction of a methoxy substitution at______is possible.

A

7-acylamino

position 3

C-7

82
Q

Semisynthetic cephalosporins can be prepared from ______

A

7‑aminocephalosporanic acid (7-ACA).

83
Q

A methyl substituent at______is good for oral absorption but bad for activity, unless a hydrophilic group is present at the α-position of the acyl side chain.

A

position 3

84
Q

True or False: ¢3-Methylated cephalosporins can be synthesized from penicillins.

A

True

85
Q

Cephamycins are cephalosporins containing a methoxy group at ______.

A

position 7.

86
Q

¢A methyl substituent at ______ is good for oral absorption but bad for activity, unless a hydrophilic group is present at the α-position of the acyl side chain.

A

position 3

87
Q

______ show moderate activity in vitro against a narrow group of Gram-negative bacteria, including P. aeruginosa and show low levels of toxicity

A

Monobactams (monocyclic β-lactams)

88
Q

True or False: Monobactums have one B lactam ring?

A

—True, showing that a fused second ring is not always essential for antibacterial activity

89
Q

______ is an example of a monobactam that has reached the clinic developed from a monobactam isolated from Chromobacterium violaceum

A

—aztreonam

90
Q

*** exam question: _____ has weak and unimportant antibiotic activity but it is a powerful and irreversible inhibitor of most β-lactamases, it is used as a sentry drug (section 14.7.1) in combination with penicillins (e.g., amoxicillin) allowing the dose levels of the penicillin to be decreased and increasing the spectrum of activity

A

Clavulanic acid

not effective against all β-lactamases

91
Q

_____ and _____ are penicillanic acid sulphone derivatives that ¢have also been developed as β‑lactamase inhibitors and are used in the clinic

A

sulbactam and tazobactam

92
Q

______ has a broader spectrum of activity against β-lactamases than clavulanic acid, but is less potent

______ is similar to sulbactam and has a similar spectrum of activity against β-lactamases, but potency more like clavulanic acid

A

sulbactam

tazobactam

93
Q

______ are:

—isolated from strains of Streptomyces olivaceus

—carbapenem structures like thienamycin (e.g., MM 13902)

—very strong inhibitors of β-lactamase, but lack chemical stability

A

Olivanic acids

94
Q

_____ is:

—first new β-lactamase inhibitor to reach the market in over 20 years

—approved in 2015 as a combination therapy with ceftazidime for the treatment of antibiotic-resistant infections of the urinary tract

—belongs to a class of compounds called the diazabicyclooctanes

—acts as a slow, reversible inhibitor

—reaction with a serine residue in the active site opens the five-membered cyclic urea, and a reversible covalent bond is formed between the ring-opened drug and the active site

A

¢Avibactam

95
Q

______, ______, and ______ —inhibit cell wall biosynthesis at different stages

A

Vancomycin, d-cycloserine and bacitracin

96
Q

Vancomycin and its binding interactions to the ______ moiety.

A

l-Lys-d-Ala-d-Ala moiety

97
Q

_______ by vancomycin cam lead to modification of the pentapeptide chain leading to resistance

A

Capping’ of pentapeptide ‘tails’

by vancomycin.

98
Q

Glycopeptides, such as ______, bind to the building blocks for cell wall synthesis, preventing their incorporation into the cell wall. They also block the cross-linking reaction for those units already incorporated in the wall. The glycopeptides are the drugs of last resort against drug-resistant strains of bacteria.

A

vancomycin

99
Q

______ binds to and inhibits the carrier lipid responsible for carrying the cell wall components across the cell membrane

_______ inhibits the synthesis of d-Ala-d-Ala.

A

Bacitracin

Cycloserine

100
Q
A

CH 456 Medicinal Chemistry (7 decks)

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