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: - Use of chemical substances against parasites in the host
• Antibioticum: Substance that is produced by a micro-organism and that:
- inhibits growth of a micro-organism (-static) or
- kills the micro-organism (-cid)
Producers of antibiotics• Actinomycetes - Streptomyces
• Bacillus - Bacillus
• Saprophytic fungi - Penicillium, Cephalosporium
Targets for some antibiotics
Group Where Target Drug
I
Outside CM
On CM
Cell wall synth- Penicillin
- Bacitracin
II Permeability
(Osmos)
- Nystatin
- Polymyxin
III Inside CM
• DNA repication
• RNA synthesis
• Protein synthesis
• Co-factor synthesis
- Nalidixic acid
- Rifampicin
- Streptomycin
- Sulfa
Penicillins (b-lactams)
CH2CO
CH CO
NH2
Pen G
Amp
R:
Penicillins (b-lactams), contNAM – NAG – NAM – NAG – NAM – NAG
L-ala
D-glu
L-lys
D-ala
D-ala
NAM – NAG – NAM – NAG – NAM – NAG
(D-ala)
D-ala
L-lys
D-glu
L-ala
Penicillins – block the synthesis
• Active only on growing cells
• Lysis of the cell
• active against both G+ and G-
• broad spectrum
• bactericidal
• Action
Penicillins (b-lactams), cont• Side effects on our cells?
• Allergy?
Penicellenic acid
protein
Penicilloyl – protein
antigen
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
Sulfanilamide PABA
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
• no receptors are available
1. Natural, artspecific resistance
• inactivating enzymes present
- Mycoplasma
- penicillinase
2. Acquired resistance - sensitive m.o resistant m.o.
Genetic processes: • 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
increased production
- sulfa
• 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
t
log OD/VC + drug
OD
VC
log OD/VC + drug
t
OD
VC
log OD/VC + drug
t
OD
VC
Effect: - static - cid - 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: -AsO4
3- 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:
E. coli R773
(plasmid)
arsR arsA arsC arsB arsD
arsR arsB arsC Chromosome
(At. caldus)
• reductase• negative regulator