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
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.

8. Timeline of Antibiotic Resistance

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

10. 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.

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

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

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

14. • Extra chromosomal genetic elements can replicate
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:

15. • 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

16. • 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

17. Decreased permeability
Porin loss
Interior of
organism
Cell
wall
Porin
channel
into
organism
Antibiot
ic
Antibiotics normally enter bacterial cells via porin channels in the
cell wall

18. Decreased permeability
Porin loss
Interior of
organism
Cell
wall
New porin
channel into
organism
Antibiot
ic
New porin channels in the bacterial cell wall do not allow
antibiotics to enter the cells

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

20. 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

21. Antibiotic inactivation
Inactivating enzymes target antibiotics
Interior of
organism
Cell
wall
Antibiotic
Target
site
Binding

22. Interior of
organism
Cell
wall
Antibiotic
Target
site
Binding
Enzyme
binding
Antibiotic inactivation
Enzymes bind to antibiotic
molecules

23. Antibiotic inactivation
Enzymes destroy antibiotics or prevent binding to
target sites
Interior of
organism
Cell
wall
Antibiotic
Target
site
Antibiotic
destroyed
Antibiotic
altered,
binding
prevented

24. • Bypass the drug resistance
Develop new
antibiotics
• Containment of drug
resistance
Judicious use of the existing
antibiotics:
Strategy to contain resistance

25. • Phage Therapy is the therapeutic use of lytic bacteriophages to
treat pathogenic bacteria infections
• Bacteriophages are viruses that invade bacterial cells 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 Staphylococcus aureus.
Alternate approach
Phage therapy