D S HIDAYAT

Department of Pharmacology & TherapeuticsFaculty of Medicine

U i it S t UtUniversitas Sumatera Utara

Basic Principles of Resistance

OUTLINES OF DISCUSSIONOUTLINES OF DISCUSSIONOUTLINES OF DISCUSSIONOUTLINES OF DISCUSSION

Mechanism of selective targeting

Pathogens, Cancer biology and Drug classes

Antineoplastic drug classes:

Mechanisms of drug resistance:

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Basic Principles of Resistance

I. Mechanism of selective targeting:

- Unique target- Selective inhibition of similar target- Common target

II. Pathogens, Cancer biology & Drug classesSites of action of antibacterial drug classes- Sites of action of antibacterial drug classes

- Stages of the viral life cycle targeted by antiviral drug classesantiviral drug classes

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Basic Principles of Resistance

III. Antineoplastic drug classes:

IV. Mechanisms of drug resistance:

G ti f d i tGenetic causes of drug resistance: - Reduced intracellular drug concentr.- Altered targeted- Insensitivity to apoptosis

Non-genetic causes of treatment failure

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Mechanism of selective targeting

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The goal of antimicrobial & antineoplasticantineoplastic

Selective toxicity

Inhibiting pathway/targets critical for pathogen (Inhibiting pathway/targets critical for pathogen ( bakteri, virus & jamur ) /cancer cell survival,

at concentration of drugat concentration of drug lower than required

to affect host pathwayto affect host pathway

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Drug Selectivity

Attacking target unique to the pathogen/ g g q p gcancer cell that not present in the host

Att ki t t i th th /Attacking targets in the pathogen/ cancer cell that are similar but not identicalthose in the hostthose in the host

Attacking targets in the pathogen/ g g p gcancer cell that are shared by the host, but that vary in importance between pathogen and host (impart selectivity)

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Drugs exhibit <<< toxicity to the host

target unique differences

D hibit t i it t th h tDrugs exhibit >>> toxicity to the host

t t thtarget common pathway

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Therapeutic index / Therapeutic windowTherapeutic index / Therapeutic window

Indication of how selective drugs in producing the desired effects

Toxic dose

Therapeutic dose

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Highly selective drug ( i illi )

g y g(penicillin)

High therapeutic index/f fMargin of safety >>>

Prescribed safelyPrescribed safely (Large difference between

therapeutic & toxic concentration)therapeutic & toxic concentration)RZH, Faculty of Medicine, USU, Medan.

Less selective drug ( th t t )

g(methotrexate)

Low therapeutic index/f fMargin of safety <<<

Prescribed carefullyPrescribed carefully (Very small difference between

therapeutic & toxic concentration)therapeutic & toxic concentration)RZH, Faculty of Medicine, USU, Medan.

Unique drug targetsU que d ug ta gets

Drug targets, genetic or biochemical pathway that is unique to pathogenpathway that is unique to pathogen

Bacterial cell wall synthesis inhibitor(peptidoglycan cell wall)

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Unique drug targetsUnique drug targets

Metabolic pathway, enzymes, t t d d d tmutated genes and gene product

(present in the pathogen/cancer cell, but lacking in the host)

Bacterial cell wall synthesis inhibitor(peptidogl can cell all)(peptidoglycan cell wall)

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Selective inhibition of similar targetg

Drug targets protein isoform that is unique to pathogenpathogen

Inhibitors of the enzyme dihydrofolate reductase (DHFR)

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Common targetsCommon targets

Drug targets, metabolic requirementthat is specific to pathogen

5-fluorouracil

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Pathogens, Cancer Cell Biology,and Drug Classesa d ug C asses

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Sites of action ofSites of action of antimicrobial drug classes

Sites of action of antimicrobial drug classesantimicrobial drug classes

Inhibit specific enzymes involved in bacterial DNA synthesis & integrity

Inhibit transcription and translation(inhibit bacterial(inhibit bacterial:

DNA-dependent RNA polymerase, 30 S ribosomal subunit,

Inhibit specific steps in bacterial

,50 S ribosomal subunit)

Inhibit specific steps in bacterial cell wall synthesis

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Antimicrobial which inhibit specific enzymes involved in

b i l DNA h i & i ibacterial DNA synthesis & integrity

Sulfonamida & trimethoprim

Formation or use of folate compoundFormation or use of folate compound that are necessary for nucleotide synthesis

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Antimicrobial which inhibit specific enzymes involved in

b i l DNA h i & i ibacterial DNA synthesis & integrity

QuinoloneQuinolone

Bacterial type II isomeraseBacterial type II isomerase

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Antimicrobial which inhibit transcription & translationtranscription & translation

Rifampin

Bacterial DNA-dependent RNA polymeraseBacterial DNA-dependent RNA polymerase

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Antimicrobial which inhibit transcription & translationtranscription & translation

Aminoglycosides,spectinomycin & tetracyclinestetracyclines

Bacterial 30S ribosomal subunit

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Antimicrobial which inhibit transcription & translationtranscription & translation

Macrolides, chloramphenicol,lincosamides streptograminslincosamides, streptogramins,

oxazolidinones

Bacterial 50S ribosomal subunit

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Antimicrobial which inhibit specific steps in bacterial p p

cell wall synthesis

Fosfomycin, cycloseriney , y

E l t i tid lEarly steps in peptidoglycan monomer synthesis

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Antimicrobial which inhibit specific steps in bacterial p p

cell wall synthesis

VancomycinVancomycin

Polymerization of peptidoglycanPolymerization of peptidoglycan (bind peptidoglycan intermediate)

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Antimicrobial which inhibit specific steps in bacterial p p

cell wall synthesis

Penicillins, cephalosporins, monobactams, carbapenemcarbapenem

Peptidoglycan crosslinkingPeptidoglycan crosslinking

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Antimicrobial which inhibit specific steps in bacterial p p

cell wall synthesis

Ethambutol, pyrazinamide, isoniazid

Process necessary for synthesis of cell wall &Process necessary for synthesis of cell wall & outer membrane of M.tuberculosis

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Bacteriostatic

D th t i hibit th th f thDrugs that inhibit the growth of pathogen without causing cell death(f i h )(for immunocompetent host)

These drugs target metabolic pathway that necessary for bacterial growth

but not for bacterial survivalbut not for bacterial survival

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Bactericidal

Drugs that kill bacteria(for immunocompromised hosts)

These drugs target metabolic pathway that necessary for bacterial growththat necessary for bacterial growth

but not for bacterial survival

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Bacteriostatic + bactericidal

Antagonistic effectsg

Th b t i t ti d t t liThe bacteriostatic drug tetracycline inhibits protein synthesis, antagonizes the

effect of cell wall synthesis inhibitor (penicillin), which requires bacterial(penicillin), which requires bacterial

growth to be effective

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Combination of two bactericidal

Synergistic effectsSynergistic effects

Penicillin + aminoglycoside (Inhibition of bacterial cell wall synthesis by ( y y

penicillin allow increased entry of aminoglycoside)allow increased entry of aminoglycoside)

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Stages of the viral glife cycle targeted by

antiviral drugsantiviral drugs

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The stages of the viral life cycletargeted by antiviral drugstargeted by antiviral drugs

1.Attachment and entry1.Attachment and entry

2.Virus become uncoated

3.Genome replication

4.Viral genes are transcribed (RNA synthesis)g ( y )

5.Virally coded RNA is translated into protein on host cell ribosomeshost cell ribosomes

6.Virion form (viral particle), which release from the host cellthe host cell

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The stages of the viral life cycletargeted by antiviral drugstargeted by antiviral drugs

1. Fusion inhibitors (enfuvirtide)

2. Inhibit virus uncoating (ion channel blocker: amantadine, rimantadine)rimantadine)

3. Inhibit viral genome replicationg p(polymerase inhibitor: acyclovir;reverse transcriptase: zidovudine &efavirenz)

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efavirenz)

The stages of the viral life cycletargeted by antiviral drugstargeted by antiviral drugs

4. Inhibit viral maturation : proteaseinhibitor (anti HIV drugs : saquinavir &ritonavir)

5. Block the relase of virus particles from5. Block the relase of virus particles from the host cell: neuramidase inhibitors

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Antineoplastic drug classes

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Antineoplastic drug classes

1.Chemoterapeutic agents interfere cell p gproliferation & rely on rapid cell cycling and/or promotion of apoptosis

2. Interfere the cell cycle in the particular phase (cell cycle spesific)phase (cell-cycle spesific) (phase M, S1, S2, G)

3. Independently of the cell cycle at a particular phase (cell cycle non-

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p p ( yspecific)

The cell cycle (4 phases)

1.M phase (M): mitosis phasep ( ) p

2. Gap 1 phase (G1): active metabolism inth b f DNA th ithe absence of DNA synthesis

3. Synthesis phase (S): DNA replication3. Synthesis phase (S): DNA replication of the cells

G 2 (G2) f S4. Gap 2 phase (G2): after completion S phase (the cell prepares for mitosis

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during the Gap 2 phase)

Cell-cycle specificity of antineoplastic drugantineoplastic drug

1.Inhibitors of microtubule function: M phase

2. Glucocorticoid : G1 phase

3. Antimetabolite & folate pathway inhibitors : S phase

4 Antitumor antibiotics: G1 phase

inhibitors : S phase

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4. Antitumor antibiotics: G1 phase

Mechanism of drug resistanceg

1 G ti1.Genetic

2.Non Genetic2.Non Genetic

Genetic causes of drug resistance

The mechanism of genetic drug resistancedrug resistance

1.Reduced intracellular concentration of drugdrug

2. Altered drug target

3. Insensitivity to apoptosis

4. Bypass metabolic requirement fortarget

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target

I. Reduced intracellular concentration of drugof drug

1. In activate drug

2. Prevent uptake activate drug

3. Promote effIuxs activate drugg

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Reduced intracellular concentration of drugof drug

1. In activate drug

Antimicrobial: inactivation of ß-lactam antibioticsinactivation of ß lactam antibiotics by ß-lactamase

A i l iAntineoplastic: inactivation of antimetabolites

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by de-aminase

Reduced intracellular concentration of drugof drug

2. Prevent uptake of drugAntimicrobial:

prevention of aminoglycoside t b lt d ientry by altered porins

Antineoplastic:Antineoplastic: decreased methotrexate entry byexpression of reduced folate

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expression of reduced folatecarrier

Reduced intracellular concentration of drugof drug

3. Promote efflux of drugAntimicrobial:

efflux of multiple drugs by MDR membrane efflux pump

Antineoplastic:Antineoplastic: efflux of multiple drugs by p170 membrane efflux pump

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membrane efflux pump

ii. Altered drug targetii. Altered drug target

Antimicrobial: i f lt d tid lexpression of altered peptidoglycan

that no longer binds vancomycin

Antineoplastic:Antineoplastic: expression of mutant DHFR that no longer bind methotrexate

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longer bind methotrexate

III. Insensitivity to apoptosisIII. Insensitivity to apoptosis

Antineoplastic: ploss of active p53

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IV. Bypass metabolic requirement for targetyp q g

Antimicrobial: inhibition of thymidylate synthaseinhibition of thymidylate synthase bypassed by exogenous thymidine

Antineoplastic: loss of estrogen receptor-dependentloss of estrogen receptor dependentgrowth results in tamoxifen resistance

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resistance

Non-genetic gcauses of

therapeutic failurep

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Non-genetic causes of therapeutic failureg p

The excessive overpriscription of antibiotics that are not indicatedantibiotics that are not indicated

for the clinical situation

Resistance involve pharmacologic and anatomical drug barriersanatomical drug barriers(the wall of abscess or the blood brain barrier)

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the blood brain barrier)

Non-genetic causes of therapeutic failureg p

Poor patient compliance(erratic drug availability found in parts of the(erratic drug availability found in parts of the

developing world)

International travel promotes a global disease community ensuring MDRdisease community, ensuring MDR

tuberculosis in all over the world

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