Antimicrobial resistance

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

3. Figure 20.20
01/23/15
GKM/KISIIU/MBSM713
/BIOC.AMIC.AGENS.LEC04
3
Antibiotic 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

6. 01/23/15
GKM/KISIIU/MBSM713
/BIOC.AMIC.AGENS.LEC04
6
A. Efflux pumps

7. 01/23/15
GKM/KISIIU/MBSM713
/BIOC.AMIC.AGENS.LEC04
7
B. Enzymatic destruction of drug

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

14. 01/23/15
GKM/KISIIU/MBSM713
/BIOC.AMIC.AGENS.LEC04
15

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

20. 01/23/15
GKM/KISIIU/MBSM713
/BIOC.AMIC.AGENS.LEC04
21
Multi-Drug Resistant TB

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