Lecture 9 Antibacterial drugs affecting nucleic acids/nucleic acid biosynthesis

Question 1

Give an example of drugs that inhibit nucleotide biosynthesis

Answer 1

sulphonamides

trimethoprim

Question 2

Give an example of drugs that inhibit bacterial DNA topoisomerases

Answer 2

Quinolones inc. fluoroquinolones

Question 3

Give an example of drugs that cause bacterial DNA damage

Answer 3

nitroimidazoles e.g. metronidazole

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 do sulfonamides inhibit?

Answer 6

GTP to dihydropteroate

Inhibits dihydropteroate synthase by binding to the PABA binding site 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

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
Hemolytic anemia in patients with an inherited glucose-6-phosphate deficiency in red blood cells

Question 12

What are side effects associated with trimethoprim

Answer 12

rash
nausea
vomiting
hypersensitivity

Question 13

What is the mode of action of quinolones and fluoroquinolones?

Answer 13

Target DNA gyrase (gyrA, gyrB) and topoisomerase 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 Bactericidal

Question 14

What is the function of DNA gyrase?

Answer 14

Catalyzes 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
Gram -ve supercoiling - relaxed DNA is coiled so that it can be packaged in bacteria

Question 15

What is the function of topoisomerase IV?

Answer 15

Catalyzes 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.
Decatenation - After replication of chromosome, the 2 daughter chromosomes interlink

Question 16

Name an example of a quinolone/fluroquinolone

Answer 16

1st gen: Nalidixic acid
2nd gen: Ciprofloxacin
3rd gen: Levofloxacin
4th gen: Moxifloxacin

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/fluoroquinolones 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/fluoroquinolones?

Answer 19

UTI

sometimes oral infections

Question 20

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

Answer 20

Most commonly used
UTIs
Prostatitis
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/fluoroquinolones?

Answer 21

Same as 2nd/3rd generations (UTIs, Prostatitis, STDs - gonorrhea/chlamydia, Skin and soft tissue infections, Bronchitis, Osteomyelitis, Enteric fever, Mycobacterial infections)
also C. difficile + S.pneumoniae

Question 22

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

Answer 22

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

Question 23

In what case are quinolone/fluoroquinolones contraindicated?

Answer 23

arthropathy - the erosion of cartilage in joints

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

Question 24

Apart from bacteria, what other parasite does metronidazole effect?

Answer 24

Protozoa

Question 25

How is metronidazole used clinically?

Answer 25

Bactericidal action against most anaerobic bacteria (and protozoa)
Active against some facultative anaerobes (can switch from aerobic to anaerobic if the environment permits)

Intra-abdo infections, C.diff, Helicobacter pylori (H. pylori)
Genital infections
Respiratory
Meningitis/brain abscesses 
Osteomyelitis
Oral/dental infections

Question 26

What is the mechanism of action of metronidazole?

Answer 26

1) Enters the cell
2) Reductive activation - reduction of nitrate via pyruvate ferredoxin oxidoreductase enzyme (PFOR)
3) = product damages DNA e.g. oxidation, strand breaks, helix destabilization

Question 27

What are the side effects of metronidazole?

Answer 27

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

Question 28

When is the use of metronidazole contraindicated?

Answer 28

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

Question 29

What are the issues surrounding metronidazole and mutogenicity?

Answer 29

Weakly mutagenic under anaerobic conditions
Some controversial reports in animals - induced carcinogenicity
No evidence of carcinogenic, mutagenic or teratogenic effects in humans

Question 30

What is the mode of action of rifamycin?

Answer 30

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

Question 31

How is rifamycin used clinically?

Answer 31

combination treatment for:
TB (+ isoniazid, pyrazinamide, ethambutol)
Leprosy (+ dapsone, clofazimine)
Penicillin-resistant S.pneumoniae (+ vancomycin)
S. aureus (+ fusidic acid)
All gram +ve

Question 32

What are the side effects of rifamycin?

Answer 32

Relatively nontoxic
Urine turns an orange-red color
Hepatitis, skin reactions, febrile effects can occur
Immunosuppressive effects seen in animal studies

Question 33

What is the antimicrobial spectrum of metronidazole?

Answer 33

Potent bactericidal action against most obligate anaerobic bacteria (and protozoa).
Active against some facultative anaerobes (microaerophiles) under anaerobic conditions.
Inactive against organisms that are aerobic or incapable of anaerobic metabolism.