Multi drug resistance

1. Evaluation seminar on MECHANISMS OF MULTI-DRUG RESISTANCE BY MALLAPPA SHALAVADI, Lucturer , HSK COLLEGE OF PHARMACY, BAGLKOT.

2. COTENTS Drug resistance Definition Types Multidrug resistance Definition Bacterial resistance to AMAs Neoplastic resistance

3. What is DRUG RESISTANCE ? It is tolerance of microorganisms to inhibitory action of antimicrobials. Natural Resistance: Some microbes have always been resistant to certain AMAs . They lack metabolic process or target site that is affected by specific drug. Eg : gram- ve bacilli are not affected by penicillin G

4. Acquired resistant: It is development of resistant by an organism due to use of an AMA over a period of time This can happen with any microbes & is major clinical problem However ;development of resistant depend on microorganism as well as drug . Resistance may be developed by mutation or gene transfer

5. Mutation: It is a stable & heritable change ,That occurs spontaneously & randomly among microorganisms. It is induced by AMA ,Any sensitive population of microorganism contains the mutant cells, which require higher concentration of AMA for inhibition single step: A single gene mutation may confirm high degree of resistance ;emerges rapidly Eg.entercocci to streptomycin and E coli to Rifampin Multistep: A number of gene modification are involved sensitivity decreases gradually in a stepwise manner .Resistant to erythromycin,tetracyclins & chloramphenicol is developed by many organism in this manner .

6. Gene transfer: Conjugation: sexual contact through the formation of bridge or sexual pilus .This may involve chromosomal or extra chromosomal (plasmid) DNA. The gene carrying the resistant or R factor is transferred only if another resistant factor is present . Transduction: It is transfer of gene carrying resistance through the agency Bacteriophage The r- factor is taken by phage & delivered to another bacteria. Eg:Penicillin ,Erythromycin are resistance to phage mediated . Transformation: A resistance carrying Bacterium may release the resistance carrying DNA into the medium & this may be imbibed by another sensitive organism-unresponsive to drug Eg : Pnemococcal resistance to penicillin G due to altered penicillin –binding protein.

7. Resistant organisms can be: Drug tolerant:- loss of affinity of the target biomolecule of the organism for a particular AMA , Eg ; resistant Staph.Aurus & E-Coli develop a RNA polymerase that does not bind to Rifampicn . Drug destroying:- The resistant microbe elaborates an enzyme which inactivates the drug Eg B- lactamases are produced by staphylococcus Hymophylus ,which inactivates Penicillin G

8. Drug impermeable:- Many hydrophobic antibiotics gain access in to the bacterial cell through specific channels formed by proteins called porins or need specific transport mechanism . Active efflux based resistant has been detected by the bacteria may also acquire plasmid directed inducible energy dependent efflux protein in their cell membrane which pump out tetracycline . Cross-resistance: Acquisition of resistance to AMA confirming resistant to another AMA ,to which the organism is not to been exposed is called cross resistant. some times unrelated drugs show partial cross-resistant Eg between tetracycline & chloramphenicol

9. MULTIDRUG RESISTANCE Multiple drug resistance or Multidrug resistance is a condition enabling a disease-causing organism to resist distinct drugs or chemicals of a wide variety of structure and function targeted at eradicating the organism. Organisms that display multidrug resistance can be pathologic cells, including bacterial and neoplastic cells. Multidrug-Resistant Organisms (MDROs) are defined as microorganisms that are resistant to one or more classes of antimicrobial agents.

10. Bacterial resistance to antibiotics Various microorganisms have survived for thousands of years by their being able to adapt to antimicrobial agents. They do so via spontaneous mutation or by DNA transfer. It is this very process that enables some bacteria to oppose the assault of certain antibiotics, rendering the antibiotics ineffective. These microorganisms employ several Mechanisms in attaining multidrug resistance: No longer relying on a glycoprotein cell wall Enzymatic deactivation of antibiotics Decreased cell wall permeability to antibiotics

11. Altered target sites of antibiotic Efflux mechanisms to remove antibiotics Increased mutation rate as a stress response

12. Enzymatic degradation Mechanisms of b - lactamase

13. Efflux mechanisms to remove antibiotics Active, energy dependent pumps can cause efflux of drugs

14. Retroviral transfer of MDR-1 confers drug Resistance:

15. The mature MDR-1 protein locates to the plasma membrane where it functions to provide ATP-dependent efflux of chemotherapeutic drugs such as etoposide , taxol and doxorubicin.

16. To limit the development of antibiotic resistance, one should: Use antibiotics only for bacterial infections Identify the causative organism if possible Use the right antibiotic; do not rely on broad-range antibiotics Not stop antibiotics as soon as symptoms improve; finish the full course Not use antibiotics for most colds, coughs, bronchitis, sinus infections, and eye infections, which are caused by viruses.

17. Neoplastic resistance Cancer cells also have the ability to become resistant to multiple different drugs, and share many of the same mechanisms: Increased efflux of drug (as by P-glycoprotein, multidrug resistance-associated protein, lung resistance-related protein, and breast cancer resistance protein) Enzymatic deactivation (i.e., glutathione conjugation) Decreased permeability (drugs cannot enter the cell) Altered binding-sites Alternate metabolic pathways (the cancer compensates for the effect of the drug).

18. Of these mechanisms common one is efflux of drugs mediated by one of energy dependent transporters, known as ATP binding cassette transporter. The ABC transporter family Functional unit contains 2 trans membrane domains and 2 nucleotde binding domains Human genome contain 48 genes that encodes ABC transporter Divided in to 7 sub families labelled A-G. This has important role in detoxification and protection of body against xenobiotics .

19. PHARMACOLOGICAL ROLE OF ABC TRANSPORTERS

20. What happened with ABC Transporters in MDR ? Certain ABC Transporter over expressed in cancer cells. Major mechanism of MDR involves P-glycoprotein, MDR associated protein-I

21. Targeting MDR cancer

22. Refererance H. P. Rang, M. M. Dale, J. M. Ritter, R. J. Flower,. Rang and Dales Pharmacology., 2009;655-660. Nature reviews, drug discovery, 3- 2006 vol 5 no. 3. www.google.com

23. Thank You