Lecture 04.2014
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The lecture discusses mechanisms of antibiotic resistance in bacteria. It covers how bacteria can develop resistance through efflux pumps to remove antibiotics, enzymatic destruction or modification of antibiotics, and alterations in antibiotic target sites to reduce drug binding. Common resistant bacteria found in hospitals and the community are also reviewed. The lecture concludes with proposals to address the growing problem of antimicrobial resistance, such as developing new antibiotics and restricting antibiotic use.
Lecture 04.2014
- 1. Lecture Four Topics: •Mechanisms of Antibiotic Resistance Dr. G. Kattam Maiyoh 01/23/15 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC04 1 MBSM 713: BIOCHEMISTRY OF ANTI MICROBIAL AGENTS
- 2. • Relative or complete lack of effect of antimicrobial against a previously susceptible microbe Antibiotic resistance • Relative or complete lack of effect of antibiotic against a previously susceptible bacreria 01/23/15 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC04 2 Antimicrobial Resistance
- 4. Drugs such as tetracyclines or erythromycins are pumped back out of bacterial cells through efflux pump proteins to keep intracellular drug concentrations below therapeutic level. The antibiotic is destroyed by chemical modification by an enzyme that is elaborated by the resistant bacteria. This is exemplified here by the beta-lactamase secreted into the periplasmic space to hydrolyse penicillin molecules before they reach their targets in the cytoplasmic membrane of Gram-negative bacterium. 01/23/15 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC04 4 Resistance strategies for bacterial survival.
- 5. The aminoglycoside antibiotic kanamycin can be enzymatically modified at three sites by three kinds of enzymatic processing — N-acetylation, O-phosphorylation or O-adenylylation — to block recognition by its target on the ribosome. The target structure in the bacterium can be reprogrammed to have a low affinity for antibiotic recognition. Here the switch from the amide linkage in the D-Ala-D- Ala peptidoglycan termini to the ester linkage in the D- Ala-D-Lac termini is accompanied by a 1,000-fold drop in drug-binding affinity. 01/23/15 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC04 5
- 8. 01/23/15 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC04 8 Enzymatic modification Aminoglycosides such as Kanamycin
- 9. 01/23/15 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC04 9 Target modification Target structure in the bacterium can be reprogrammed to have a low affinity for antibiotic recognition
- 10. • Enzymatic destruction of drug • Prevention of penetration of drug • Alteration of drug's target site • Rapid ejection of the drug (efflux) • Resistance genes – alter 01/23/15 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC04 11 No penetration Summary of mechanism of resistance
- 11. 01/23/15 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC04 12 Antibiotic Selection for Resistant Bacteria
- 12. 1. Exposure to sub-optimal levels of antimicrobial 2. Inappropriate antibiotic use (see next page) 3. Exposure to microbes carrying resistance genes 01/23/15 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC04 13 What Factors Promote Antimicrobial Resistance?
- 13. • Prescribing practices of providers e.g. use of broad spectrum antibiotics and prescribing without a laboratory request or doctor visit. • Prescription not taken correctly • Antibiotics for viral infections – common cold • Antibiotics sold without medical supervision • Spread of resistant microbes in hospitals due to lack of hygiene • Concerns of daycare providers (need to restrict access). 01/23/15 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC04 14 Examples for resistance
- 15. • Lack of quality control in manufacture or outdated antimicrobial • Inadequate surveillance or defective susceptibility assays • Poverty or war • Use of antibiotics in foods 01/23/15 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC04 16 Other examples for resistance
- 16. –Growth promotion –Disease prevention –Sick animal treatment/plants – very large amounts –Poultry –Fish farms –Fruit, potatoes, tobacco and others –Ornamental plants 01/23/15 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC04 17 Role of antibiotics use in agriculture
- 17. 01/23/15 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC04 18 Should antibiotics for growth promotion and disease prevention be banned? • Adverse effect on animal industry • Reduced food supply • Increased cost of production • Increased disease incidence economic loss by farmers • May not be totally necessary • Might only require ban of specific antimicrobial drugs that could select for resistance to drugs in human medicine.
- 18. Consequences of Antimicrobial Resistance • Infections resistant to available antibiotics • Increased cost of treatment 01/23/15 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC04 19
- 19. 01/23/15 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC04 20 Current problems of Resistance/MDR bacteria Hospital Community Gram Negative Gram Negative Acinetobactor sp. E. Coli Citrobacter sp. Neisseria gonorrhoeae Enterobacter sp. S. typhi Klebsiella sp. S. tythimurium P. aeruginosa Serratia marcescens Gram Positive Gram Positive Enterococcus sp.: vancomycin resistant enterococci (VRE) Enterococcus sp.: vancomycin resistant enterococci (VRE) Coagulase negative staphylococcus Mycobacterium turberculosis MRSA MRSA MRSA heterogenously resistant to vancomycin Streptococcus pneumoniae Streptococcus pyogenes
- 21. • Methicillin-Resistant Staphylococcus aureus • Most frequent nosocomial (hospital-acquired) pathogen • Usually resistant to several other antibiotics 01/23/15 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC04 22 MRSA “mer-sah”
- 22. • Speed development of new antibiotics • Track resistance data nationwide • Restrict antimicrobial use • Direct observed dosing (TB) 01/23/15 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC04 23 Proposals to Combat Antimicrobial Resistance
- 23. • Use more narrow spectrum antibiotics • Use antimicrobial cocktails • Tx only the sick or at risk • Producer education • Further research before imposing bans 01/23/15 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC04 24 Proposals to combat antimicrobial resistance
- 24. • Antimicrobial peptides – Antibiotics from plants and animals • Squalamine (sharks) • Protegrin (pigs) • Magainin (frogs) • DNA technology • Antisense agents – Complementary DNA or peptide nucleic acids that binds to a pathogen's virulence gene(s) and prevents transcription – Phage therapy - use of bacteriophages to treat pathogenic bacterial infections 01/23/15 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC04 25 The Future of Chemotherapeutic Agents
- 25. Thank you for your attention 01/23/15 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC04 26
Editor's Notes
- #19: Increased disease incidence, may see more foodborne pathogens.