Inhibitors of Nucleic Acid And Others Flashcards
Other unclassified antibiotics.?
Nitrofurans
Rifamycin
Metronidazole
Polymixins
What drugs are known as DNA synthesis inhibitors
Sulphonamides
Diaminopyramidines
Quinolones
In the past what methods and countries had activities resembling antibiotics.
Chaulmoogra oil (from seeds) – treatment of leprosy in India since ancient times
Mercury – treatment for syphilis since 16th century
Other topical antiseptics – too toxic for systemic use
What did Paul Ehrlich do?
Since parasites could be differentiated from tissues of the infected host by laboratory dyes, such substances might display preferential affinity for the parasites in the body as well”
(Protosil red)
First to propose need for selective toxicity….
Discovery of the first antibacterial agent,
Protosil red, a sulponamide bound to a red dye, able to stain bacteria.
Cured mice of haemolytic strep.
But no in vitro activity, in vivo (body) sulphonamide released an active agent
Sulphanomides, what do they do and how is this antibiotic?
Sulphonamides prevent folic acid (needed for purines) production and therefore DNA synth. (Bacteriostatic).bacteria cannot uptake formed folic acid, must produce!
NB: mammals revive this nutrient from diet, can’t produce!
What are the requirements of folic acid for DNA synth.
folate is converted in tetrohydrofolate (THF)
THF co-factor to nucleotides biosynthesis
can transfer CH- or CHO- groups of nucleotides precursors during synthesis
Sulphanomides pro’s and action/how
Broad spectrum bacteriostatics
Block folate synthesis
Sulph. Competes for binding
Folate depletion - fail to prod. Purine nucleotides and thymidine
Sulphonamides con’s and action/how?
Slow to work - folate deplete generation
Sometimes combined with trimethoprim , etc
Side effects of sulphanomides
Steven Johnson syndrome
Inflam. Of skin and mucous membranes
Severe morbidity, can be fatal ..
Diaminopyrimadines : tripmethoprim
functions and interactions?
inhibit di-hydrofolate - late stage folate syth.
higher affinity for bacterial enzyme, than mammalian
trimethoprim - usage and side effects?
broad spectrum bacteriostatic
side effects rare
mostly used >uti, sometimes + sulphonamides
(e.g. co-trimaxazole) act on two loci in same pathway
… pobably as effective and less toxic alone!!
co- trimoxazole
(trimethoprim + sulphonamide)
interactions/usage and side effects?
both drugs synergist of one another
neither active against pseudomonas sp.
pneumonacytis - pneumonia AIDS
S.E: bone marrow toxicity same as chloramphenicol.
used rarely: only when sp. is resistant to Blactams & ciprofloxacin..
Quinalones: Fammily of natural synthetic broad spectrum drugs how do they work?
they interact and prevent bacterial DNA from unwinding and replicating
quinolones all share an essential structure but…
all have variable R groups
NB, if flouroine is this molecule: flouroquinolone
Quinolones: Nalidixin acid
usage and implications?
activity against G-ive except pseudomonas aureginosa.
well absorbed orally - exreted in urine.
used to treat UTI.
2 alterationss improved activity.
flouroquinolones usage and implicaions?
active vs. G+ive & G-ive (+pseudomonas aureginosa)
oral administration
well distributed through tissues.
Concenrated in mammalian cells (intra infections) chlamydia, legionella and some mycobacteria
flouroquinolones resistance and side effects?
R: recommend minimal use, held in reserve 4 resistants.
S.E: rashes, GI upset, non-specific neurological problems
• Not recommended for children or pregnant women
– Alter deposition of cartilage: damage musculoskeletal system
• Some have had to be withdrawn due to unexpected toxicity
flouroquinalones - target?
gram-ive : target DNA topoisomerase type II (DNA gyrase), with topoisomerase type IV as 2nd target!
Gram +ive (opposite) - Type IV primary target, type II, 2nd.
Enzyme activity:
DNA gyrase: without it DNA supercoils.
Topoisomerase II/IV - unlinks DNA during replication.
flouroquinolones - mode of action
binds (enzyme - DNA) complex.
inhibits function.
release of broken DNA strand..
Fluoroquinolones - resistance ..?
• Usually due to chromosomal mutation
• Modified structure of DNA gyrase and topoisomerase IV
• Decrease membrane permeability – downregulation of outer membrane porin
proteins
• Overactive efflux pumps actively removing drug
how do drugs manage to Inhibit DNA synthesis?
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 PDG or “different ribosomes”
Nitrofurans - usages
• Nitrofurantoin – UTIs only
• Oral dosage followed by rapid excretion in the urine, also inactivated in tissues
• Active against Gram negative and positive urinary pathogens – except Proteus sp. and Pseudomonas sp.
• More active in acidic conditions
Nitrofurans - resistance ?
Resistance uncommon
• Side effect – nausea
• Mode of action uncertain
• Possible the nitro compound is reduced by the organism – affects DNA
