Nucleic Acid Inhibitors

Front 1

Sulponamides - basis

Back 1

•Analogue of para-aminobenzoic acid (PABA)•Essential for folic acid synthesis

•Mammalian cells use preformed folic acid and cannot synthesize

•Bacteria synthesize and cannot take up folic acid preformed

Front 2

Sulphonamides - spectrum of activity

Back 2

•Broad spectrum bacteristatic

Front 3

Sulphonamides - mechanism of activity ?

Back 3

•Block stage in folate synthesis (inhibits dihydropteroate synthase)

•Sulphonamides competitive binding

•Folate depletion – failure to produce purine nucleotides and thymidine

Front 4

Three enzyme in folate synthesis

1) DHPS

2) DHFS

3) DHFR

enzyme 1 and three can be inhibited via ?

Back 4

1) Sulphonomides

2) -

3) Trimethoprim

Front 5

Sulphonamides -why do they take a long time to work?

Back 5

•need folate depletion which can take a few generations.

Front 6

Sulphonamides - commonly used in combination with

Back 6

Trimethoprim

Front 7

Sulphonamides - side effects

Back 7

•Stevens-Johnson Syndrome

- inflammation of the skin andmucous membranes.

•Eg eyes, digestive system, lungsand respiratory system (can be fatal)

Front 8

Trimethoprim - mechanism of action ?

Back 8

•Inhibit dihydrofolate reductase – later stage infolate synthesis

•Much higher affinity for the bacterial enzyme than the mammalian

Front 9

Trimethoprim - spectrum of activity ?

Back 9

•Broad spectrum bacteristatic

Front 10

Trimethoprim - side effects ?

Back 10

rare

Front 11

Trimethoprim witha Sulphonamide - mechanism?

-e.g. co-trimoxazole

to treat ......

-e.g. UTI

Back 11

•to act at 2 locations in the same pathway (folate systesis pathway)

•but probably as effective and less toxic alone

Front 12

Co-trimoxazole-

(Trimethoprim + sulphamethoxazole)

- demonstrate ............

Back 12

•synergy

Front 13

(Trimethoprim + sulphamethoxazole)

spectrum of activity ?

Back 13

•Rarely used in UK, but sometimes when resistance to beta lactams andciprofloxacin have occured

+ Pneumocystis carinii, fungal pneumonia, AIDS

-neither are active against Pseudomonas

Front 14

Inhibitorsof nucleic acid synthesis

-mechanism of action

Back 14

•Interfere with DNA and RNA functions

•(May be due to different pathways)

•Different structure of bacterial genome

•Enzymes not possessed by mammalian cells

•Important due to universal nature of the target•Not PeptiDoGlycan or “different ribosomes”

Front 15

Quinolones - names/types

Back 15

- Nalidixic acid

- Norfloxacin

- Ciprofloxin

Front 16

Quinolones - spectrum of activity?

Back 16

•Gram negatives – except pseudomonas

•Used exclusively for UTIs

Front 17

Quinolones -

Well absorbed ..........., excerted in .........

Back 17

• orally , urine

Front 18

2 alterations improved activity:

Back 18

•A F in C6( flumequine)

•Piperazineat C7 (pipemicidic acid)

•C7 can very but F a constant

•Fluoroquinolones

Front 19

Fluoroquinolones - spectrum of activity ?

Back 19

•Gram positive and Gram negative including Pseudomonas

•Largely replaced quinolones which showed little G+ve activity

Front 20

Fluoroquinolones - names/types ?

Back 20

•Ciprofloxacin, moxifloxacin

Front 21

Fluoroquinolones - ROA?

Back 21

•Oral administration

Front 22

Fluoroquinolones -

well distributed through tissue & concentrated in mammalian cells , thus good for treating ?

Back 22

intracellular pathogens :

•(chlamydia, legionella, some mycobacteria)

•Antibiotic of choice for typhoid fever

Front 23

Fluoroquinolones - resistance ?

Back 23

•becoming a problem ( especially when used in animal husbandry)

Front 24

Fluoroquinolones - mechnism of action ?

Back 24

•Gram negatives – target DNA topoisomerase type II (gyrase) with type IVas a secondary target.

•Gram positives – opposite

Front 25

DNAgyrase (type II) does what ?

Back 25

•supercoiling

Front 26

Topioisomerase TypeIV does what?

Back 26

replication,recombination and repair

Front 27

Fluoroquinolones - resistance mechanisms?

Back 27

•Resistance usually due to chromosomal mutation

•Modified structure of type II and IV

•Decrease membrane permeability

•Over-reactive efflux pumps actively removing drug

Front 28

Fluoroquinolones - side effects

Back 28

•Side effects – rashes, gastrointestinal and non specific neurologicalsymptoms

•Not recommended for children or pregnant

•Some have had to be withdrawn due to unexpected toxicity

Front 29

Nitrofurans- spectrum of activity ?

(N.B: More active in acidic conditions)

Back 29

•Active against Gram negative and positive urinary pathogens only – exceptProteus and Pseudomonas

•Oral dosage followed by rapid excretion in the urine, also inactivatedin tissues

(NOT intra-cellulars!)

Front 30

Nitrofurans - resistance ?

Back 30

•Resistance uncommon

Front 31

Nitrofurans - side effects

Back 31

• nausea

Front 32

Nitrofurans - mechanism of action ?

Back 32

uncertain ?

-•Possible the nitro compound is reduced by the organism – affects DNA

Front 33

Rifampicin - mechanism of action

Back 33

•Binds to Beta subunit of DNA-dependant RNA polymerase – inhibits mRNAsynthesis

Front 34

Rifampicin - ROA

Back 34

well absorbed orally

Front 35

Rifampicin - spectrum of activity ?

Back 35

•Active against Myco tuberculosis and leprae, staphylococci, legionella

Front 36

Rifampicin - resistance?

Back 36

occursrapidly – used in combination •Unfortunately resistance can occur due to mutations in this subunit which is encoded on thechromosome

•So often used with other agents

•But useful for determining frequency of point mutations is a species

Front 37

Rifampicin - used to treat

Back 37

-TB,leprosy, Legionnaires disease and staphylococcal infections (never alone)

- Prophylaxis against meningococcal and Haemophillus influenzae type b disease

Front 38

Rifampicin - side effects?

Back 38

•hepatotoxicity can occur

•Interfere with other drugs handled by the liver – oral contraceptives

•Pigmentation can lead to red bodily secretions

Front 39

Abrief look at Mycobacteria

•Issues: waxy coat, slow growing, tendency to survive with macrophages .

use what drugs?

Back 39

•General: include Rifampicin and Streptomycin.

•Also some macrolides and fluoroquinolones

-Specific :Isoniazid, ethambutol, cycloserine ( if first line fails)

Front 40

A brief look at Mycobacteria

•Issues: waxy coat, slow growing, tendency to survive with macrophages .

WHY? do we use these drugs

Back 40

•Hard to study due to growth rate.

•Mode of actions, inhibit cell wall formation? Isoniazid..mycolic acids

•Ethambutol … arabinoalacatan inhibitory

•target DNA topoisomerase type II (gyrase)

• inhibition of bacterial protein biosynthesis

Front 41

Metronidazole- spectrum of activity ?

Back 41

•Active against anaerobes

Front 42

Metronidazole - reistance ?

Back 42

•Resistance uncommon

Front 43

Metronidazole - mode of action

Back 43

uncertain– possible reduction product formed at low redox potential induce DNA strandbreakage

Front 44

Metronidazole - side effects with alcohol

Back 44

•nausea and vomiting, vasodilatation, flushing, headaches, palpitations, tachycardia

Front 45

Metronidazole - side effects without alcohol

Back 45

•Damages DNA , genotoxic and tumourogenic,while no evidence, avoid use in pregnancy

Front 46

Membraneactive agents - names/types

Back 46

•Polymixins

•PolymixinB and Colisitin (E)

•Polypeptides with long hydrophobic tail

Front 47

Membrane active agents-

mechanism of activity ?

Back 47

•Bind to cell membrane causing leakage of cytoplasm

Front 48

Membrane active agents- harmful?

Back 48

•Considerable toxicity

Front 49

Membrane active agents- spectrum of activity ?

Back 49

•Active against Gram negatives except Proteus – including inactiveorganisms

Front 50

Membrane active agents- ROA

Back 50

•Systemic use limited, im injection

•Used topically

Front 51

Polymixin B and Colisitin can be used to eradicate ............... infection in patients groups?

Back 51

Pseudomonas infections in CF patients