Action of and Resistance to drugs and toxic metals

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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
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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)

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Producers of antibiotics

• Actinomycetes

- Streptomyces

• Bacillus

- Bacillus

• Saprophytic fungi

- Penicillium, Cephalosporium
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Targets for some antibiotics




Where
Target
Group
Drug
I
- Penicillin - Bacitracin
Outside CM
Cell wall synth
Permeability (Osmos)
- Nystatin - Polymyxin
II
On CM

• DNA repication
• RNA synthesis
• Protein synthesis
• Co-factor synthesis

• Nalidixic acid
• Rifampicin
• Streptomycin
• Sulfa

III
Inside CM
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Penicillins (b-lactams)
R
Pen G
Amp
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Penicillins (b-lactams), cont

• Action

Penicillins block the synthesis

• Active only on growing cells

• active against both G and G-
• broad spectrum
• bactericidal

• Lysis of the cell

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Penicillins (b-lactams), cont

• Side effects on our cells?

• Allergy?

Penicellenic acid
?
Penicilloyl protein
antigen
protein
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Streptomycin

• active against both G and G-
• broad spectrum
• bactericidal

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Streptomycin, cont.

• Targets (translation)

• initiation complex
• binding to 30S subunit

RpsL-protein

• Results

• misstranslation
• faulty proteins

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Streptomycin, cont.

• Used clinically?

• selldom
• against TBC

• dizziness (balance difficulties)
• lowering the hearing

• Side effects

Note! The 80S ribosome is not effected!
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Sulfa drug

• Sulfa drugs not antibiotics produced
  chemically
• Growth factor analog

PABA
Sulfanilamide
Folic acid (vitamin)
CoF
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Sulfa drug, cont.

• Acts as a competetive inhibitor in synthesis of
  Folic acid

• CoF participates in several biosynthetic
  reactions aa, purins etc.

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Type of resistance
1. Natural, artspecific resistance

• no receptors are available

- Mycoplasma

• inactivating enzymes present

- penicillinase
2. Acquired resistance
- sensitive m.o ? resistant m.o.
Genetic processes

• mutation
• transformation
• transduction
• conjugation

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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
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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

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Effect on a growing cultur
OD
OD
OD
VC
VC
VC
Effect
- static
- cid
- lytic
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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

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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.

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Mercuric resistance, cont.
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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)

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Arsenic resistance, cont.

• Genetic

E. coli R773 (plasmid)
Chromosome (At. caldus)

• reductase

• negative regulator