Lecture 9 Antibacterial drugs affecting nucleic acids/nucleic acid biosynthesis Flashcards
Give an example of drugs that inhibit tetrahydrofolate biosynthesis
sulphonamides
trimethoprim
Give an example of drugs that inhibit bacterial DNA supercoiling and decatenation
Quinolones inc. fluoroquinolones
Give an example of drugs that cause bacterial DNA damage
nitroimidazoles and nitrofurans e.g. methronidazole, nitrofurantoin
Give an example of drugs that inhibit RNA synthesis
rifamycins
Why is tetrahydrofolate production important in bacteria
essential for the production of DNA
Which step in the pathway of tetrahydrofolate production does sulfonamides inhibit?
GTP to dihydropteroate
Inhibits dihydropteroate synthase by binding to the PABA binding site (analogue) at a higher affinity
Which step in the pathway of tetrahydrofolate production does trimethoprim inhibit?
Dihydrofolate to tetrahydrofolate
Inhibits dihydrofolate reductase enzyme (analogue)
What is the advantage of using trimethoprim and sulfonamides together?
used alone = bacteriostatic
Used together = bacteriocidal (synergistic effect)
How are sulfonamides selective to bacteria
Humans do also need tetrahydrofolate but the pathway of production is different
GTP to dihydropteroate does not exist in the human pathway
What are the clinical uses of trimethoprim and sulfonamides?
First line treatment/prophylaxis for pneumocystis jiroveci pneumonia in HIV
UTI
Sometimes resp and GI tract infections and malaria due to plasmodium falciparum
What are side effects associated with sulfonamides
Hypersensitivity
Drug induced fever
Steven-Johnson syndrome
Haemolytic anaemia in patients with inherited glucose-6-phosphate deficiency in red blood cells
What are side effects associated with trimethorpim
rash
nausea
vomiting
hypersensitivity
What is the mode of action of quinolones and fluroquinolones?
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
What is the function of DNA gyrase?
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
What is the function of topoisomerase IV?
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
Name an example of a quinolone/fluroquinolone
Ciprofloxacin
Explain the relationship between DNA gyrase/topoisomerase IV and gram +ve/-ve
Gyrase is the primary target for gram -ve
Topoisomerase IV is the primary target for gram +ve
Why are quinolones/fluroquinolones specific?
humans do not have DNA gyrase
Humans have topoisomerase IV but it has a different structure
What are the clinical uses of 1st generation quinolone/fluroquinolones?
UTI
sometimes oral infections
What are the clinical uses of 2nd and 3rd generation quinolone/fluroquinolones?
Most commonly used UTIs Prosatitis STDs - gonorrhea/chlamydia Skin and soft tissue infections Bronchitis Osteomyelitis Enteric fever Mycobacterial infections
What are the clinical uses of 4th generation quinolone/fluroquinolones?
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
What are side effects that can occur from quinolone/fluroquinolones?
Generally well tolerated GI distubances CNS toxicity Phototoxicity Hypotension Tachycardia Haematological changes Drug interactions Interference with caffeine metabolism Tendonitis
In what case arequinolone/fluroquinolones contraindicated?
arthopathy - erosion of cartilage in joints
Shown in young animals = contraindicated in pregnant woman, nursing mothers, adolescents
What are the 2 main drugs used clinically from the nitrohetercyclic class?
Nitroimidazoles - metronidazole
Nitrofurans - nitrofurantoin
Apart from bacteria, what other parasite does metronidazole effect?
Protazoa
How is metronidazole used clinically?
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
What is the mechanism of action of metronidazole?
Enters the cell
Reduction activation - reduction of nitrate via pyruvate ferredoxin oxidoreductase enzyme
= DNA damage from product e.g. oxidation, strand breaks, helix destabilisation
What are the side effects of metronidazole?
Normally well tolerated GI disturbances CNS effects reversible neutropenia Enhancement of anticoagulant effects of warfarin
When is use of metronidazole contraindicated?
Alcohol - disulfiram (used to treat alcoholism) like reaction where metronidazole blocks alcohol oxidation = accumulation of acetaldehyde in the blood stream
Pregnancy - teratogen
What are the issues surrounding metronidazole and mutogenicity?
Weakly mutagenic under anaerobic conditions
Some reports in animals
No evidence in humans
What is the mechanism of action of nitrofuran drugs?
reductively activated = DNA damage
Can be aerobic conditions
How is nitrofurantoin used clinically?
Broad spectrum
UTI - treatment or prophylaxis for recurrent cases
Rapidly excreted
What are the side effects of nitrofurantoin?
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
What is the mode of action of rifamycin?
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
How is rifamycin used clinically?
combination treatment for: TB Leprosy Penicillin resistant S. pneumoniae S. aureus
All gram +ve
What are the side effects of rifamycin?
Relatively non toxic
Urine turns a orange-red colour
Hepatits, skin reactions, febrile effects can occur
Immunosupressive effects seen in animal studies
