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BMSC2210 - Chemotherapy > L8 - Antibacterials : nucleic acid (biosynthesis) > Flashcards

L8 - Antibacterials : nucleic acid (biosynthesis) Flashcards

1
Q

What are drugs that inhibit nucleotide biosynthesis?

A

Sulphonamides

trimethoprim

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2
Q

What are drugs that inhibit bacterial DNA topoisomerase

A

Quinolones

fluoroquinolones

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3
Q

What are drugs that cause bacterial DNA damage?

A

Nitroimidazoles (metronidazole)

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4
Q

What are drugs that inhibit RNA synthesis?

A

Rifamycins

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5
Q

What are the synergistic effects of trimethopim and sulfonamides?

A

show greater inhibition of bacterial growth

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6
Q

What is the first example of sulfa drugs?

A

prontosil - red azo dye

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7
Q

What do sulfa drugs do?

A

competitively inhibit DHPS
alternative substrate to PABA

make a Dead End Complex that CANNOT MAKE TETRAHYDROFOLATE

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8
Q

What is the original molecule used for synthesis of DHPS?

A

PABA

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9
Q

What is Trimethoprim?

A

synthetic

SINGLE MEMBER

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10
Q

How does Trimethoprim work?

A

competitively inhibit dihydrofolic acid - stops reduction to tetrahydrofolic acid which is essential in thymidine synthesisi

catalysed by dihydrofolate reductase - binds to it

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11
Q

How is Trimethoprim selective?

A

bacteria need 5-15nM for 50% inhibition

humans need 300,000nM

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12
Q

Clinical applications of sulfonamides and trimethoprim?

A

treatment of respiratory, urinary, digestive tract infections

pneumonia in HIV

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13
Q

Why are sulfonamides and trimethoprim now limited?

A

resistance

adverse reactions

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14
Q

What are the 2 enzymes involved in altering DNA topology?

A

Type II topoisomerases

DNA gyrase
DNA topo IV

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15
Q

What are the functions of the 2 topoisomerases?

A

A2B2 heterotetramers

catalysed ATP-dependent double-strand breakage/rejoining interactions

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16
Q

How does DNA Topo IV work?

A

forms transient double strand break in one ring of catenated DNA

other molecule passes through

process = splitting of chromosomes

17
Q

How does DNA gyrase work?

A

supercoils related DNA

allows DNA to be sufficiently compacted to fit into bacterial cell

also regulates gene expression

18
Q

Mode of action of quinolones?

A

usually enzymes cleave dsDNA at 4bp staggered sites

5’ ends temporarily tethers then reseals

quinolones bind to 5’ ends & stabilise complex

base stacking with 5’ end of molecule

magnesium ion in quinolone - co-ordinate 4 water mols - can be close to top of enzyme and interact

these enzyme residues are well conserved in bacteria

19
Q

Why are quinolones selective?

A

human residues are different to bacterial residues - quinolone does not interact

Type II topoisomerases = A2 dimers, not A2B2

no gyrase

20
Q

What are additional aspects of quinolone action?

A

blocks DNA replication & transcription

Bactericidal

21
Q

What are the most widely used quinolones?

A

CIPROFLOXACIN
NORFLOXACIN
OFLOXACIN

22
Q

What do 2nd gen quinolones (ciprofloxacin) target?

A

chlamydia
Mycoplasma
Gram pos cocci
Gram neg rods

23
Q

Clinical application of 2nd gen quinolones?

A

respiratory infections

anthrax

gonorrhea

GTIs

UTIs

24
Q

Adverse side effects of quinolones?

A

CNS toxicity
phototoxicity
tachycardia
tendon rupture

ARTHROPATHY - erode cartilage, not shown in humans but STILL not used in children

25
Q

What is the most used class of Nitroheterocycling drugs?

A

Nitroimidazoles

26
Q

How were nitroimidazoles discovered?

A

used for parasitic STIs e.g. Trichomonas

also treated a ladies bacterial gingivitis

27
Q

What part fo nitroimidazole responsible for antibacterial activity?

A

Nitro group

28
Q

What is metronidazole effective against?

A

OBLIGATE ANAEROBIC BACTERIA (protozoa)

some facultative anaerobes

29
Q

Why can’t metronidazole work against aerobes?

A

oxygen antagonises the antibacterial effect

30
Q

How does metronidazole work?

A

Nitro group = electron acceptor

reduced by low-redox nitroreductases (PFOR)

31
Q

What are toxic effects of metronidazole?

A

DNA DAMAGE
oxidation
strand breaks
destabilise helix

32
Q

Clinical applications of metronidazole?

A

treat anaerobic bacteria (fat list on slides)

protozoal infections

33
Q

adverse side effects of Metronidazole?

A

GTI disturbances
CNS effects
neutropenia

BAD REACTION ALCOHOL - accumulation of acetylaldehyde

mutate bacteria - carcinogenicity (animals)

34
Q

How do rifamycins work?

A

Bind beta subunit of prokaryotic RNA polymerase

when RNA reaches 3NTs in length - abortive initiation

prompts enzyme to fail and start again

bactericidal

35
Q

What is the most important rifamycin?

A

Rifampicin/Rifampin

36
Q

clinical applications of rifamycins?

A

WITH OTHER DRUGS

TB
Leprosy
Penicillin-resistant S. pneumoniae
S. aureus

relatively non-toxic

37
Q

Adverse side effects of rifamycin?

A

hepatitis
skin reactions
febrile reaction
immunosuppressive effects

1/3 of dose in urine - RED URINE

BMSC2210 - Chemotherapy (17 decks)

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