Download Action of and Resistance to drugs and toxic metals

Action of and Resistance to drugs
and toxic metals
by
E. Börje Lindström
This learning object has been funded by the European Commissions FP6 BioMinE project
Definitions
• Chemoterapi:
• Antibioticum:
- Use of chemical substances against parasites in the host
Substance that is produced by a microorganism and that:
- inhibits growth of a micro-organism
(-static) or
- kills the micro-organism (-cid)
Producers of antibiotics
• Actinomycetes
• Bacillus
• Saprophytic fungi
- Streptomyces
- Bacillus
- Penicillium, Cephalosporium
Targets for some antibiotics
Group
Where
Outside CM
Target
Cell wall synth
Drug
- Penicillin
I
- Bacitracin
II
III
On CM
Inside CM
Permeability
- Nystatin
(Osmos)
- Polymyxin
• DNA repication
- Nalidixic acid
• RNA synthesis
- Rifampicin
• Protein synthesis
- Streptomycin
• Co-factor synthesis
- Sulfa
Penicillins (b-lactams)
R:
CH2
CH
NH2
CO
CO
Pen G
Amp
Penicillins (b-lactams), cont
• Action
NAM – NAG – NAM – NAG – NAM – NAG
L-ala
D-glu
L-lys
(D-ala)
D-ala
D-ala
D-ala
L-lys
Penicillins – block the synthesis
D-glu
L-ala
NAM – NAG – NAM – NAG – NAM – NAG
• Active only on growing cells
• active against both G+ and G• broad spectrum
• Lysis of the cell
• bactericidal
Penicillins (b-lactams), cont
• Side effects on our cells?
• Allergy?
Penicellenic acid  Penicilloyl – protein
antigen
protein
Streptomycin
• active against both G+ and G• broad spectrum
• bactericidal
Streptomycin, cont.
• Targets (translation):
- initiation complex
- binding to 30S subunit
RpsL-protein
• Results:
- misstranslation
- faulty proteins
Streptomycin, cont.
• Used clinically?
-selldom
- against TBC
• Side effects:
-dizziness (balance difficulties)
- lowering the hearing
Note! The 80S ribosome is not effected!
Sulfa drug
• Sulfa drugs – not antibiotics – produced chemically
• Growth factor analog
PABA
Sulfanilamide
Folic acid
(vitamin)
CoF
Sulfa drug, cont.
• Acts as a competetive inhibitor in synthesis of Folic acid
• CoF participates in several biosynthetic reactions – aa,
purins etc.
Type of resistance
1. Natural, artspecific resistance
• no receptors are available
• inactivating enzymes present
2. Acquired resistance
Genetic processes:
- Mycoplasma
- penicillinase
- sensitive m.o  resistant m.o.
• mutation
• transformation
• transduction
• conjugation
Type of resistance, cont.
Biochemical mechanisms for acquired resistance:
• permeability changes of OM or CM
- penG, tetracyclin, actinomycin D
• alternative biosynthesis or
- sulfa
increased production
• changed receptor
- streptomycin
• enzym production
- penicillinase
Properties of a good antibioticum
• Broad spectrum
• Prevent resistant mutants to arise
• Have no side effects on the human cell
• Leave the flora of our body intact
Effect on a growing cultur
log OD/VC
+ drug
log OD/VC
OD
+ drug
log OD/VC
+ drug
OD
OD
VC
VC
t
t
Effect:
- static
VC
- cid
t
- lytic
Combined usage of antibiotics
• Antagonism
-drugs acting against each other
- (-cid) + (-static)
- e.g. Penicillin & kloramphenicol/ sulpha
• Synergism
- drugs enhancing their effect
- (-cid) + (-cid)
- e.g. penicillin + streptomycin
Mercuric resistance
• Action:
-Bind to SH- groups
- inhibits synthesis of macro molecules
- most sensitiva are transcription and translation
• Resistance:
-usually plasid mediated
- both in G+ and G-; S.aureus, Pseudomonads, At. thioxidans
- enzymatic reduction; Hg2+  Hg0
- Hg0 less toxic
- in organic mercury , C-Hg, Hg is first removed with the
enzyme lyas.
Mercuric resistance, cont.
Arsenic resistance
• Action:
-AsO43- ions are transported into the cell via
- phosphate-transport system
- analog to PO43- ions
- inhibits different kinases
• Resistance:
- plasmid mediated
- AsO43- is reduced to AsO2- AsO2- is effluxed (transported to the outside)
Arsenic resistance, cont.
• Genetic:
arsR arsD arsA arsB arsC
E. coli R773
(plasmid)
arsR arsB arsC
Chromosome
(At. caldus)
• negative regulator
• reductase