Lecture 9 Antibacterial drugs affecting nucleic acids/nucleic acid biosynthesis

Question 1

Give an example of drugs that inhibit tetrahydrofolate biosynthesis

Answer 1

sulphonamides

trimethoprim

Question 2

Give an example of drugs that inhibit bacterial DNA supercoiling and decatenation

Answer 2

Quinolones inc. fluoroquinolones

Question 3

Give an example of drugs that cause bacterial DNA damage

Answer 3

nitroimidazoles and nitrofurans e.g. methronidazole, nitrofurantoin

Question 4

Give an example of drugs that inhibit RNA synthesis

Answer 4

rifamycins

Question 5

Why is tetrahydrofolate production important in bacteria

Answer 5

essential for the production of DNA

Question 6

Which step in the pathway of tetrahydrofolate production does sulfonamides inhibit?

Answer 6

GTP to dihydropteroate

Inhibits dihydropteroate synthase by binding to the PABA binding site (analogue) at a higher affinity

Question 7

Which step in the pathway of tetrahydrofolate production does trimethoprim inhibit?

Answer 7

Dihydrofolate to tetrahydrofolate

Inhibits dihydrofolate reductase enzyme (analogue)

Question 8

What is the advantage of using trimethoprim and sulfonamides together?

Answer 8

used alone = bacteriostatic

Used together = bacteriocidal (synergistic effect)

Question 9

How are sulfonamides selective to bacteria

Answer 9

Humans do also need tetrahydrofolate but the pathway of production is different
GTP to dihydropteroate does not exist in the human pathway

Question 10

What are the clinical uses of trimethoprim and sulfonamides?

Answer 10

First line treatment/prophylaxis for pneumocystis jiroveci pneumonia in HIV
UTI
Sometimes resp and GI tract infections and malaria due to plasmodium falciparum

Question 11

What are side effects associated with sulfonamides

Answer 11

Hypersensitivity
Drug induced fever
Steven-Johnson syndrome
Haemolytic anaemia in patients with inherited glucose-6-phosphate deficiency in red blood cells

Question 12

What are side effects associated with trimethorpim

Answer 12

rash
nausea
vomiting
hypersensitivity

Question 13

What is the mode of action of quinolones and fluroquinolones?

Answer 13

Target DNA gyrase (gyrA, gyrB) and topisomerase IV (parC, parE)
Specifically binds into the ‘quinolone binding pocket’ - where the staggered cuts have been made via base stacking = complex can no longer rejoin
Therefore supercoiling and decatenation does not occur

Blocks DNA replication/transcription therefore Bacteriacidal

Question 14

What is the function of DNA gyrase?

Answer 14

Catalyses ATP dependent DNA double strand breakage/rejoining reactions
Cuts at 4 base pair staggered sites on the double stranded DNA - the enzyme then binds to the 5’ end via a tyrosine residue
-ve supercoiling - relax DNA is coiled so that it can be packaged in bacteria

Question 15

What is the function of topoisomerase IV?

Answer 15

Catalyses ATP dependent DNA double strand breakage/rejoining reactions
Cuts at 4 base pair staggered sites on the double stranded DNA - the enzyme then binds to the 5’ end via a tyrosine residue
Decatination - After replication of chromosome, the 2 daughter chromosomes interlink

Question 16

Name an example of a quinolone/fluroquinolone

Answer 16

Ciprofloxacin

Question 17

Explain the relationship between DNA gyrase/topoisomerase IV and gram +ve/-ve

Answer 17

Gyrase is the primary target for gram -ve

Topoisomerase IV is the primary target for gram +ve

Question 18

Why are quinolones/fluroquinolones specific?

Answer 18

humans do not have DNA gyrase

Humans have topoisomerase IV but it has a different structure

Question 19

What are the clinical uses of 1st generation quinolone/fluroquinolones?

Answer 19

UTI

sometimes oral infections

Question 20

What are the clinical uses of 2nd and 3rd generation quinolone/fluroquinolones?

Answer 20

Most commonly used
UTIs
Prosatitis
STDs - gonorrhea/chlamydia
Skin and soft tissue infections
Bronchitis
Osteomyelitis
Enteric fever
Mycobacterial infections

Question 21

What are the clinical uses of 4th generation quinolone/fluroquinolones?

Answer 21

Same as 2nd/3rd generations (UTIs, Prosatitis, STDs - gonorrhea/chlamydia, Skin and soft tissue infections,, Bronchitis, Osteomyelitis, Enteric fever, Mycobacterial infections)
also includes intra-abdo infections
Pneumonia

Question 22

What are side effects that can occur from quinolone/fluroquinolones?

Answer 22

Generally well tolerated
GI distubances
CNS toxicity
Phototoxicity
Hypotension
Tachycardia
Haematological changes
Drug interactions
Interference with caffeine metabolism
Tendonitis

Question 23

In what case arequinolone/fluroquinolones contraindicated?

Answer 23

arthopathy - erosion of cartilage in joints

Shown in young animals = contraindicated in pregnant woman, nursing mothers, adolescents

Question 24

What are the 2 main drugs used clinically from the nitrohetercyclic class?

Answer 24

Nitroimidazoles - metronidazole

Nitrofurans - nitrofurantoin

Question 25

Apart from bacteria, what other parasite does metronidazole effect?

Answer 25

Protazoa

Question 26

How is metronidazole used clinically?

Answer 26

Bactericidal action against most anaerobic bacteria (and protazoa) Active against some facultative anaerobes (can switch from aerobic to anaerobic if the environment permits) ``` Intra-abdo infections, C.diff, H.pylori Genital infections Resp Meningitis/brain abscesses Osteomylitis Oral/dental infections ```

Question 27

What is the mechanism of action of metronidazole?

Answer 27

Enters the cell Reduction activation - reduction of nitrate via pyruvate ferredoxin oxidoreductase enzyme = DNA damage from product e.g. oxidation, strand breaks, helix destabilisation

Question 28

What are the side effects of metronidazole?

Answer 28

``` Normally well tolerated GI disturbances CNS effects reversible neutropenia Enhancement of anticoagulant effects of warfarin ```

Question 29

When is use of metronidazole contraindicated?

Answer 29

Alcohol - disulfiram (used to treat alcoholism) like reaction where metronidazole blocks alcohol oxidation = accumulation of acetaldehyde in the blood stream Pregnancy - teratogen

Question 30

What are the issues surrounding metronidazole and mutogenicity?

Answer 30

Weakly mutagenic under anaerobic conditions Some reports in animals No evidence in humans

Question 31

What is the mechanism of action of nitrofuran drugs?

Answer 31

reductively activated = DNA damage | Can be aerobic conditions

Question 32

How is nitrofurantoin used clinically?

Answer 32

Broad spectrum UTI - treatment or prophylaxis for recurrent cases Rapidly excreted

Question 33

What are the side effects of nitrofurantoin?

Answer 33

Nausea/vomiting allergic reaction Haemolytic anaemia - rare Pulmonary reactions (acute/chronic) - rare Mutagenicity/carcinogenicity - produces double stranded breaks in human DNA under anaerobic cells for older drugs, no evidence in humans now

Question 34

What is the mode of action of rifamycin?

Answer 34

Bacteriacidal effect in most bacteria | Binds to beta subunit of RNA polymerase = blocks the exit tunnel for RNA release, this is known as abortive initation

Question 35

How is rifamycin used clinically?

Answer 35

``` combination treatment for: TB Leprosy Penicillin resistant S. pneumoniae S. aureus ``` All gram +ve

Question 36

What are the side effects of rifamycin?

Answer 36

Relatively non toxic Urine turns a orange-red colour Hepatits, skin reactions, febrile effects can occur Immunosupressive effects seen in animal studies