Antibiotic resistance

Mechanistic view of antibiotic resistance

1. Mechanistic View of Antibiotic Resistance Muhammad Mubashar Noor Abdul Qadeer Enam Ullah

2. Introduction From the beginning there has been a continuous battle between human beings and micro-organisms that cause infection and disease in humans, animals and plants.

3. History Nobel Lecture, December 11, 1945 In his 1945 Nobel Prize lecture, Fleming said “It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them, and the same thing has occasionally happened in the body and by exposing microbes to non-lethal quantities of the drug make them resistant.” Sir Alexander Fleming The Nobel Prize in Physiology or Medicine 1945

4. Why resistance is a concern Resistant organisms lead to treatment failure Increased mortality Resistant microorganisms may spread in Community Low level resistance can go undetected Added burden on healthcare costs Threatens to return to pre-antibiotic era

5. Drug Resistance Drug resistance occurs in: Bacteria (Antibiotic Resistance) Endoparasites Virus (Resistance to antiviral drugs) Fungi Cancer cells

6. Antibiotic Resistance Antibiotic resistance happens when the germs no longer respond to the antibiotics designed to kill them . That means the germs are not killed and continue to grow.

7. Timeline of Antibiotic Resistance

8. Myths of Antibiotic Resistance Drugs (antibiotics) cause organisms antibiotic resistant. Antibiotic resistant organisms are more virulent.

9. Truth Antibiotics select out the resistant strain Faulty use of antibiotics or widespread use of antibiotics increases the probability of such selection. Antibiotic resistant strains appear to be more virulent because we cannot kill them or stop their growth.

10. Mechanism Antibiotic Resistance Intrinsic (Natural) Acquired Genetic Methods Chromosomal Methods Mutations Extra chromosomal Methods Plasmids

11. Lack target : No cell wall; innately resistant to penicillin Innate efflux pumps: Drug blocked from entering cell or export of drug (does not achieve adequate internal concentration). Eg. E. coli , P. aeruginosa Drug inactivation: Cephalosporinase in Klebsiella It occurs naturally Intrinsic resistance

12. Mutations : It refers to the change in DNA structure of the gene Occurs at a frequency of one per ten million cells O ften mutants have reduced susceptibility Acquired resistance It occurs due to

13. E x t r a c h r omo s oma l g enetic el e me n ts c an r epli c at e independently and freely in cytoplasm. Plasmids which carry genes resistant ( r-genes ) are called R- plasmids . These r-genes can be readily transferred from one R-plasmid to another plasmid or to chromosome. Much of the drug resistance encountered in clinical practice is plasmid mediated . Plasmids:

14. Transfer of r-genes from one bacterium to another Conjugation Transduction Transformation Transfer of r-genes between plasmids within the bacterium By transposons By Integrons Mechanisms of resistance gene transfer

15. Prevention of drug accumulation in the bacterium Modification/protection of the target site Use of alternative pathways for metabolic / growth requirements By producing an enzyme that inactivates the antibiotic Biochemical mechanisms of antibiotic resistance

16. Decreased permeability Porin l oss Interior of organism Cell wall Porin channel into organism Antibiotic Antibiotics normally enter bacterial cells via porin channels in the cell wall

17. Decreased permeability Porin l oss Interior of organism Cell wall New porin channel into organism Antibiotic New porin channels in the bacterial cell wall do not allow antibiotics to enter the cells

18. Structurally modified antibiotic target site Interior of organism Cell wall Target site Bin d ing Antibiotic Antibiotics normally bind to specific binding proteins on the bacterial cell surface

19. Structurally modified antibiotic target site Interior of organism Cell wall Modified target site Antibiotic Changed site: blocked binding Antibiotics are no longer able to bind to modified binding proteins on the bacterial cell surface

20. Antibiotic inactivation Inactivating enzymes target antibiotics Interior of organism Cell wall Antibiotic Target site Bind i ng

21. Interior of organism Cell wall Antibiotic Target site Bind i ng Enzy m e binding Antibiotic inactivation Enzymes bind to antibiotic molecules

22. Antibiotic inactivation Enzymes destroy antibiotics or prevent binding to target sites Interior of organism Cell wall Antibiotic Target site Antibiotic d e stro y ed Antibiotic altered, binding prevented

23. Strategy to contain resistance

24. Phage Therapy is the therapeutic use of lytic bacteriophages to treat pathogenic bacteria infections Bac t erioph a g es a r e vi r use s th a t i nv ade bac t erial c e lls and disrupt bacterial metabolism and cause the bacterium to lyse Bacteriophage therapy is an important alternative to antibiotics The success rate was 80–95% with few gastrointestinal or allergic side effects. British studies also demonstrated significant efficacy of phages against Escherichia coli , Acinetobacter spp ., Pseudomonas spp ., and Staphylococc us aureus . Alternate approach Phage therapy