L8 - Antibacterials : nucleic acid (biosynthesis)

Question 1

What are drugs that inhibit nucleotide biosynthesis?

Answer 1

Sulphonamides

trimethoprim

Question 2

What are drugs that inhibit bacterial DNA topoisomerase

Answer 2

Quinolones

fluoroquinolones

Question 3

What are drugs that cause bacterial DNA damage?

Answer 3

Nitroimidazoles (metronidazole)

Question 4

What are drugs that inhibit RNA synthesis?

Answer 4

Rifamycins

Question 5

What are the synergistic effects of trimethopim and sulfonamides?

Answer 5

show greater inhibition of bacterial growth

Question 6

What is the first example of sulfa drugs?

Answer 6

prontosil - red azo dye

Question 7

What do sulfa drugs do?

Answer 7

competitively inhibit DHPS
alternative substrate to PABA

make a Dead End Complex that CANNOT MAKE TETRAHYDROFOLATE

Question 8

What is the original molecule used for synthesis of DHPS?

Answer 8

PABA

Question 9

What is Trimethoprim?

Answer 9

synthetic

SINGLE MEMBER

Question 10

How does Trimethoprim work?

Answer 10

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

catalysed by dihydrofolate reductase - binds to it

Question 11

How is Trimethoprim selective?

Answer 11

bacteria need 5-15nM for 50% inhibition

humans need 300,000nM

Question 12

Clinical applications of sulfonamides and trimethoprim?

Answer 12

treatment of respiratory, urinary, digestive tract infections

pneumonia in HIV

Question 13

Why are sulfonamides and trimethoprim now limited?

Answer 13

resistance

adverse reactions

Question 14

What are the 2 enzymes involved in altering DNA topology?

Answer 14

Type II topoisomerases

DNA gyrase
DNA topo IV

Question 15

What are the functions of the 2 topoisomerases?

Answer 15

A2B2 heterotetramers

catalysed ATP-dependent double-strand breakage/rejoining interactions

Question 16

How does DNA Topo IV work?

Answer 16

forms transient double strand break in one ring of catenated DNA

other molecule passes through

process = splitting of chromosomes

Question 17

How does DNA gyrase work?

Answer 17

supercoils related DNA

allows DNA to be sufficiently compacted to fit into bacterial cell

also regulates gene expression

Question 18

Mode of action of quinolones?

Answer 18

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

Question 19

Why are quinolones selective?

Answer 19

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

Type II topoisomerases = A2 dimers, not A2B2

no gyrase

Question 20

What are additional aspects of quinolone action?

Answer 20

blocks DNA replication & transcription

Bactericidal

Question 21

What are the most widely used quinolones?

Answer 21

CIPROFLOXACIN
NORFLOXACIN
OFLOXACIN

Question 22

What do 2nd gen quinolones (ciprofloxacin) target?

Answer 22

chlamydia
Mycoplasma
Gram pos cocci
Gram neg rods

Question 23

Clinical application of 2nd gen quinolones?

Answer 23

respiratory infections

anthrax

gonorrhea

GTIs

UTIs

Question 24

Adverse side effects of quinolones?

Answer 24

CNS toxicity
phototoxicity
tachycardia
tendon rupture

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

Question 25

What is the most used class of Nitroheterocycling drugs?

Answer 25

Nitroimidazoles

Question 26

How were nitroimidazoles discovered?

Answer 26

used for parasitic STIs e.g. Trichomonas also treated a ladies bacterial gingivitis

Question 27

What part fo nitroimidazole responsible for antibacterial activity?

Answer 27

Nitro group

Question 28

What is metronidazole effective against?

Answer 28

OBLIGATE ANAEROBIC BACTERIA (protozoa) some facultative anaerobes

Question 29

Why can't metronidazole work against aerobes?

Answer 29

oxygen antagonises the antibacterial effect

Question 30

How does metronidazole work?

Answer 30

Nitro group = electron acceptor reduced by low-redox nitroreductases (PFOR)

Question 31

What are toxic effects of metronidazole?

Answer 31

DNA DAMAGE oxidation strand breaks destabilise helix

Question 32

Clinical applications of metronidazole?

Answer 32

treat anaerobic bacteria (fat list on slides) protozoal infections

Question 33

adverse side effects of Metronidazole?

Answer 33

GTI disturbances CNS effects neutropenia BAD REACTION ALCOHOL - accumulation of acetylaldehyde mutate bacteria - carcinogenicity (animals)

Question 34

How do rifamycins work?

Answer 34

Bind beta subunit of prokaryotic RNA polymerase when RNA reaches 3NTs in length - abortive initiation prompts enzyme to fail and start again bactericidal

Question 35

What is the most important rifamycin?

Answer 35

Rifampicin/Rifampin

Question 36

clinical applications of rifamycins?

Answer 36

WITH OTHER DRUGS TB Leprosy Penicillin-resistant S. pneumoniae S. aureus relatively non-toxic

Question 37

Adverse side effects of rifamycin?

Answer 37

hepatitis skin reactions febrile reaction immunosuppressive effects 1/3 of dose in urine - RED URINE