Basic overview on Mechanisms of drug resistance

1. Done by,
Revathy Nandakumar
2nd MSc. Bioinformatics
Union Christian College
Aluva, Kerala

2. Antibiotic Resistance
 Repeated use of chemicals often leads to their
ineffectiveness due to onset of resistance or
tolerance
 Major challenge to pharmaceutical companies
Drug Resistance
Intrinsic
resistance
Acquired
resistance

4. Intrinsic drug resistance
Organism naturally possess the ability to tolerate a
particular drug
Due to:-
 Structure of cell membrane
 Existence of drug transport protein
 Absence of metabolic pathway
 Presence of drug-metabolizing enzyme
 High expression of stress response protein or
repair mechanisms
E.g. Mammalian lung withstand damage caused
Oxygen-free radicals

5. 1. Self-protection mechanisms and IDR
Organism toxic drug inactivated
Attained by, => inactivation of antibiotics (streptomycin
& neomycin) by phosphotransferases and acetyl
transferases
E.g. Streptomyces antibiotic resistance

6. 2. Chemically- induced adaptive change and IDR
Drugs Organism Biochemical changes
Drug resistance Time lag
Attained by=> enzyme induction and DNA repair&
detoxification
E.g. β- lactam antibiotic exposed bacteria show
increase in chromosomally encoded penicillinases
NB: Short lived; normally effect is reversed when toxic
agent is removed

7. 3. Physiological stress response and IDR
Heat
Anoxia
U.V, pH
Stress etc.
Genetic reflex Drug resistance
transient hyperthermia/heat-shock proteins or genes
(HSP90,HSP70,HSP20)drug resistance
E.g. HSP90 interact with ’dioxin’ receptor mediates induction
of drug metabolizing enzymes

8. Acquired drug resistance
Resistant strain emerges from population that was
previously drug sensitive.
Arise by:
i. Mutation and amplification of specific genes involved
in protective pathway
ii. Mutation in genes which regulate stress response
iii. Gene transfer

9. 1. Natural Selection and ADR
Random mutation
Large Bacterial population Few survived and naturally selected
It is a requirement for mutation and biological variation.
i.e. drug resistant individuals outgrow susceptible
counterparts
E.g. In E.coli, structural changes in penicillin binding protein
can result in resistance to antibiotics such as mecillinam and
cephalosporin
Drug

10. 2. Drug mediated genetic changes and ADR
Some drugs are mutagenic (anti-cancer drugs)
This could increases the frequency of mutation leading to
the development of resistant cells.
E.g. Frequency of DNA amplification increases on exposure
to irradiations, alkylating agents etc.

11. 3. Adaptive drug resistance in pre-neoplastic cells
Drug resistance in some mammalian cells arise due to
mutation or modification to adaptive response
E.g. In the hepatocarcinogenic events in rodents, there
observed a pre-neoplastic hepatocyte nodules.
This nodules arise from carcinogen contacting
environment that could give them drug resistance

12. Biochemical mechanisms of Drug resistance

13. i. Reduced drug delivery
ii. Decreased drug uptake
iii. Increased drug efflux
iv. Reduced metabolic activation of drug
v. Sequestration of drug to prevent interaction with
target site
vi. Increase in intracellular concentration of target site
vii. Structural alteration of target site and etc..

14. Let’s Watch…

15. Strategies to overcome drug resistance
1.MDR modulators
2. siRNA based therapies
3. Nano particulate Drug Delivery Systems(DDS)

17. Thank you…