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