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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:. - Use of chemical substances against parasites in the host. Antibioticum:.

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Action of and Resistance to drugs and toxic metals

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  1. 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

  2. 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)

  3. Producers of antibiotics • Actinomycetes - Streptomyces • Bacillus - Bacillus • Saprophytic fungi - Penicillium, Cephalosporium

  4. 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

  5. CH CO CH2 CO NH2 Penicillins (b-lactams) R: Pen G Amp

  6. NAM – NAG – NAM – NAG – NAM – NAG L-ala D-glu L-lys D-ala D-ala (D-ala) D-ala L-lys D-glu L-ala NAM – NAG – NAM – NAG – NAM – NAG 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

  7. Penicillins (b-lactams), cont • Side effects on our cells? • Allergy? Penicellenic acid  Penicilloyl – protein antigen protein

  8. Streptomycin • active against both G+ and G- • broad spectrum • bactericidal

  9. Streptomycin, cont. • Targets (translation): • initiation complex • binding to 30S subunit RpsL-protein • Results: • misstranslation • faulty proteins

  10. Streptomycin, cont. • Used clinically? • selldom • against TBC • dizziness (balance difficulties) • lowering the hearing • Side effects: Note! The 80S ribosome is not effected!

  11. Sulfa drug • Sulfa drugs – not antibiotics – produced chemically • Growth factor analog PABA Sulfanilamide Folic acid (vitamin) CoF

  12. Sulfa drug, cont. • Acts as a competetive inhibitor in synthesis of Folic acid • CoF participates in several biosynthetic reactions – aa, purins etc.

  13. 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

  14. 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

  15. 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

  16. + drug + drug + drug log OD/VC log OD/VC log OD/VC t t t Effect on a growing cultur OD OD OD VC VC VC Effect: - static - cid - lytic

  17. 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

  18. Mercuric resistance • Action: • Bind to SH- groups • inhibits synthesis of macro molecules • most sensitiva are transcriptionand 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.

  19. Mercuric resistance, cont.

  20. 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)

  21. arsR arsD arsA arsB arsC arsR arsB arsC Arsenic resistance, cont. • Genetic: E. coli R773 (plasmid) Chromosome (At. caldus) • reductase • negative regulator

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