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CH 456 Medicinal Chemistry > Chapter 19 Antibacterial Agents > Flashcards

Chapter 19 Antibacterial Agents Flashcards

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
True or False: Sulphonamides are bacteriocidal
False, bacteriostatic
26
\_\_\_\_\_\_\_ is the most widely prescribed sulphonamide today
sulphamethoxazole sulphamethoxazole and trimethoprim (inhibits dihydrofolate reductase (DHFR), are often co-formulated and administered together \*known as sequential blocking
27
True or False: Sulphonamides and trimethoprim both inhibit synthesis of tetrahydrofolate
True
28
How are sulfonamides competitive enzyme inhibitors
Sulphonamide prevents PABA from binding by mimicking PABA.
29
The _______ or the\_\_\_\_\_\_ involves the design of chemicals which show selective toxicity against bacterial cells rather than mammalian cells.
principle of chemotherapy magic bullet
30
Early antibacterial agents were \_\_\_\_\_, \_\_\_\_\_\_, and \_\_\_\_\_\_\_.
salvarsan, prontosil, and the sulphonamides
31
Following the discovery of penicillin, several classes of antibiotics were isolated from \_\_\_\_\_\_\_.
fungal strains.
32
\_\_\_\_\_\_require a primary aromatic amine group and a secondary sulphonamide group for good activity.
Sulphonamides
33
True or False: Adding an aromatic or heteroaromatic group to the sulphonamide nitrogen provides a variety of sulphonamides with different pharmacokinetic properties.
True
34
\_\_\_\_\_\_ of sulphonamides is a common metabolic reaction.
N-Acetylation
35
Sulphonamides are used to treat infections of the\_\_\_\_\_, ______ and \_\_\_\_\_\_\_.
urinary tract, gastrointestinal tract, and mucous membranes.
36
\_\_\_\_\_\_ 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.
Mammals Bacteria
37
Sulphones are used in the treatment of \_\_\_\_\_\_.
leprosy
38
\_\_\_\_\_\_ 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
β-lactam
39
\_\_\_\_\_\_ contain a β-lactam fused to a 5-membered thiazolidine ring with a sulphur atom
Penicillin penicillin V normally as its potassium salt
40
What are the 4 components of penicillin structure?
Acyl side chain β-lactam ring Thiazolidine ring 6-APA
41
Penicillin inhibits cross-linking of bacterial cell walls by irreversibly reacting with the enzyme \_\_\_\_\_\_\_
transpeptidase
42
penicillin G is acid-sensitive so it can not be administered what way?
Orally
43
Why is it hard to counteract acid sensitivity?
cannot alter ring strain or the highly reactive β-lactam carbonyl group
44
How do you counteract acid sensitivity?
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
\_\_\_\_\_\_ 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
Phenoxymethylpenicillin (penicillin V)
46
What are the 5 resistance mechanisms to penicillins?
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
What are two examples of physical barriers that cause penicillin resistance?
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
The use of ______ to block penicillin from reaching the β-lactamase active site enzymes.
steric shields (bulky group)
49
\_\_\_\_\_ and ______ have a positively charged amino group that enhances their uptake through bacterial porin channels
ampicillin and amoxicillin
50
True or False: both ampicillin and amoxicillin compounds are acid resistant
True, because of the presence of the electron-withdrawing amino group so can be given orally
51
True or False: both ampicillin and amoxicillin have steric shields
False, therefore they are sensitive to β‑lactamase enzymes
52
\_\_\_\_\_ was the first carboxypenicillin
carbenicillin
53
Why is there a broad spectrum of carboxypenicillins?
due to the hydrophilic carboxylic acid group
54
\_\_\_\_\_ and ______ are prodrugs for carbenicillin and show an improved absorption through the gut wall
carfecillin and indanyl carbenicillin
55
ticarcillin is similar carbenicillin, but has a ______ ring
thiophene
56
Penicillins have a ______ structure consisting of a β-lactam ring fused to a thiazolidine ring
bicyclic structure
57
Penicillin analogues can be prepared by ______ or by a \_\_\_\_\_\_\_\_
fermentation semi-synthetic synthesis from 6-aminopenicillanic acid.
58
Variation of the penicillin structure is limited to the \_\_\_\_\_\_\_.
acyl side chain
59
True or False: Penicillins can be made more resistant to acid conditions by incorporating an electron-withdrawing group into the acyl side chain.
True
60
\_\_\_\_\_ activity is associated with the presence of an α‑hydrophilic group on the acyl side chain of penicillin.
Broad spectrum
61
\_\_\_\_\_\_\_ 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
Cephalosporins
62
\_\_\_\_\_ was the first cephalosporin discovered isolated from fungus found in sewer waters in Sardinia
Cephalosporin C
63
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
True therefore viewed as useful lead compound for development of more potent broad spectrum antibiotics
64
What are the 4 parts of the cephalosporins ?
Aminoadipic side chain B-lactam ring Dihydrothiazane ring 7-ACA
65
What is the mechanism by which cephalosporins inhibit the transpeptidase enzyme?
Through aminoadipic side chain
66
\_\_\_\_\_\_\_ 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
First-generation cephalosporins e.g., cephalothin, cephaloridine, cephalexin, cefazolin
67
What are the 3 types of second generation cephalosporins?
cephamycins cefoxitin oximinocephalosporins
68
\_\_\_\_\_\_contain an advantageous methoxy substituent at position 7
cephamycins
69
True or False: unlike most cephalosporins, cephamycins are effective against anaerobic microbes
True
70
parent compound ____ was isolated Streptomyces clavuligerus
cephamycin C the first β-lactam to be isolated from a bacterial source (stabilizes neighbouring carbonyl group)
71
\_\_\_\_\_ has broader spectrum of activity than most first-generation cephalosporins due to greater resistance to β-lactamase enzymes
cefoxitin may be due to the steric hindrance provided by the methoxy group
72
\_\_\_\_\_ provided major advance in cephalosporin research and contain an iminomethoxy group at the α-position of the acyl side chain
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
\_\_\_\_\_\_ cephalosporins are modified oximinocephalosporins
Third-generation replacing furan ring with an aminothiazole ring
74
In third generation cephlapsorins, by replacing the furan ring with an aminothiazole ring what happens?
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
\_\_\_\_\_ and _____ are fourth generation cephalosporins
cefepime and cefpirome
76
oximinocephalosporins (4th generation) that are ______ compounds having a positively charged substituent at position 3 and a negatively charged carboxylate group at position 4
zwitterionic \*this appears to radically enhance the ability of these compounds to penetrate the outer membrane of Gram-negative bacteria
77
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.
True
78
\_\_\_\_\_\_ cephalosporins has activity against various strains of MRSA and multidrug-resistant Streptococcus pneumonia (MDRSP) and acts as a prodrug for ceftaroline
Fifth-generation, ceftaroline fosamil
79
In fifth-generation cephalosporins, the ______ is thought to be important for its activity against MRSA
1,3-thiazole ring
80
Know this chart
81
¢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.
7-acylamino position 3 C-7
82
Semisynthetic cephalosporins can be prepared from \_\_\_\_\_\_
7‑aminocephalosporanic acid (7-ACA).
83
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.
position 3
84
True or False: ¢3-Methylated cephalosporins can be synthesized from penicillins.
True
85
Cephamycins are cephalosporins containing a methoxy group at \_\_\_\_\_\_.
position 7.
86
¢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.
position 3
87
\_\_\_\_\_\_ show moderate activity in vitro against a narrow group of Gram-negative bacteria, including P. aeruginosa and show low levels of toxicity
Monobactams (monocyclic β-lactams)
88
True or False: Monobactums have one B lactam ring?
—True, showing that a fused second ring is not always essential for antibacterial activity
89
\_\_\_\_\_\_ is an example of a monobactam that has reached the clinic developed from a monobactam isolated from Chromobacterium violaceum
—aztreonam
90
\*\*\* 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
Clavulanic acid not effective against all β-lactamases
91
\_\_\_\_\_ and _____ are penicillanic acid sulphone derivatives that ¢have also been developed as β‑lactamase inhibitors and are used in the clinic
sulbactam and tazobactam
92
\_\_\_\_\_\_ 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
sulbactam tazobactam
93
\_\_\_\_\_\_ are: ## Footnote —isolated from strains of Streptomyces olivaceus —carbapenem structures like thienamycin (e.g., MM 13902) —very strong inhibitors of β-lactamase, but lack chemical stability
Olivanic acids
94
\_\_\_\_\_ is: ## Footnote —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
¢Avibactam
95
\_\_\_\_\_\_, \_\_\_\_\_\_, and ______ —inhibit cell wall biosynthesis at different stages
Vancomycin, d-cycloserine and bacitracin
96
Vancomycin and its binding interactions to the ______ moiety.
l-Lys-d-Ala-d-Ala moiety
97
\_\_\_\_\_\_\_ by vancomycin cam lead to modification of the pentapeptide chain leading to resistance
Capping’ of pentapeptide ‘tails’ by vancomycin.
98
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.
vancomycin
99
\_\_\_\_\_\_ binds to and inhibits the carrier lipid responsible for carrying the cell wall components across the cell membrane ## Footnote \_\_\_\_\_\_\_ inhibits the synthesis of d-Ala-d-Ala.
Bacitracin Cycloserine
100

CH 456 Medicinal Chemistry (7 decks)

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