AMD-resistance

1. Antimicrobial drugs:
Cellular & molecular Mechanism of
action
and
Resistance
SUMIT KUMARSUMIT KUMAR
Integral UniversityIntegral University

2. Antimicrobial Drug Resistance
(AMDR)
Resistance is said to be developed whenResistance is said to be developed when
microbes are less treatable with one or moremicrobes are less treatable with one or more
medication used to treat or prevent infection.medication used to treat or prevent infection.

3. Classes of AMDR
Antifungal drug resistanceAntifungal drug resistance
Antiviral drug resistanceAntiviral drug resistance
Antiprotozoal drug resistanceAntiprotozoal drug resistance
Antibacterial / antibiotic drugsAntibacterial / antibiotic drugs
resistanceresistance
 Multidrug resistance (MDR)Multidrug resistance (MDR)

4. Consequences of
AMDR
1. Medication against which microbes1. Medication against which microbes
developed resistance become lessdeveloped resistance become less
effective in both treating and preventingeffective in both treating and preventing
infection .infection .
2. Resistant microbes may require other2. Resistant microbes may require other
medications / higher doses –often withmedications / higher doses –often with
more side-effects.more side-effects.
3. Some infection become completely3. Some infection become completely

5. Mechanisms of
resistance
Microbes can resist an Antimicrobial agents byMicrobes can resist an Antimicrobial agents by
1.1. alteration in receptor of drugalteration in receptor of drug
Ex :B lactam resistance (alteration in receptorsEx :B lactam resistance (alteration in receptors
of penicillin)of penicillin)
2.2. decreasing the amount of drug that reachesdecreasing the amount of drug that reaches
the receptor by altering the entry / increasingthe receptor by altering the entry / increasing
removal of the drugremoval of the drug
Ex: tetracyclines resistance, aminogylcosidesEx: tetracyclines resistance, aminogylcosides
resistance.resistance.

6. 3.3. destroying / inactivating the drugdestroying / inactivating the drug
Ex: B lactam resistance (penicillinase enzymeEx: B lactam resistance (penicillinase enzyme
alter B lactam ring structure of penicillin &alter B lactam ring structure of penicillin &
cephalosporins, inactivate the drug),cephalosporins, inactivate the drug),
chloramphenicol resistancechloramphenicol resistance
(chloramphenicol transacetylate causes(chloramphenicol transacetylate causes
formation of acetylated chlormphenicol,formation of acetylated chlormphenicol,
which binds less well to 50 s ribosome)which binds less well to 50 s ribosome)
4.4. developing resistant metabolic pathwaysdeveloping resistant metabolic pathways

7. Molecular mechanisms of
antimicrobial resistance

8. Quinolone resistance
Caused by mutation in DNA gyrase subunit ACaused by mutation in DNA gyrase subunit A
/ B, reduced outer membrane permeability in/ B, reduced outer membrane permeability in
gm –ve cellsgm –ve cells
Newer Fluoroquinolones resistance-Newer Fluoroquinolones resistance-
chromosomal mutation , causing amino acidchromosomal mutation , causing amino acid
substitution in A subunit of DNA gyrase.substitution in A subunit of DNA gyrase.

9. Sulfonamide –Trimethoprim
resistance
Sulfonamide resistance due to pointSulfonamide resistance due to point
mutation / acquisition of plasmid that causesmutation / acquisition of plasmid that causes
synthesis of new enzyme: Altered / newsynthesis of new enzyme: Altered / new
dihydropteroic synthase that has poor affinitydihydropteroic synthase that has poor affinity
for sulfonamides & preferentially binds tofor sulfonamides & preferentially binds to
PABAPABA
Trimethoprim resistance due to acquisition ofTrimethoprim resistance due to acquisition of
new plasmid , production of alterednew plasmid , production of altered
dihydrofolate reductase with reduced affinitydihydrofolate reductase with reduced affinity
for trimethoprim.for trimethoprim.

10. Rifampicin resistanceRifampicin resistance
Resistance of bacteria to rifampicin isResistance of bacteria to rifampicin is
caused by an alteration in one amino acid incaused by an alteration in one amino acid in
DNA directed RNA polymerase, which resultsDNA directed RNA polymerase, which results
in reduced binding of rifampicin.in reduced binding of rifampicin.
B lactams resistanceB lactams resistance
Presence of altered penicillin binding proteinsPresence of altered penicillin binding proteins
(receptors),which binds penicillin less well in(receptors),which binds penicillin less well in
penicillin resistant S pneumoniae.penicillin resistant S pneumoniae.

11. Cellular & molecular
mechanism of Antimicrobial action
 Microbial cells grow & divide, replicateMicrobial cells grow & divide, replicate
repeatedly to reach the large numbersrepeatedly to reach the large numbers
presents during an infection.presents during an infection.
 To grow & divide microbes must synthesizeTo grow & divide microbes must synthesize
many types of biomolecules.many types of biomolecules.
 Antimicrobials agents/ drugs interfere withAntimicrobials agents/ drugs interfere with
specific processes that are essential forspecific processes that are essential for
growth & division.growth & division.

12. Antimicrobials acts by interfering
with:
1)1) Cell wall synthesisCell wall synthesis ex: Penicillins &ex: Penicillins &
cephalosporins (inhibit peptidoglycancephalosporins (inhibit peptidoglycan
polymerization),Vancomycin ( combines withpolymerization),Vancomycin ( combines with
cell wall substrates)cell wall substrates)
2)2) Plasma membrane integrityPlasma membrane integrity ex: polymyxinsex: polymyxins
(disrupt plasma membrane, causing(disrupt plasma membrane, causing
leakage), polyenes (amphotericin) &leakage), polyenes (amphotericin) &
imidazoles (ketoconazole, clotrimazole)imidazoles (ketoconazole, clotrimazole)
{plasma membrane sterols of fungi are{plasma membrane sterols of fungi are
attacked by drugs}attacked by drugs}

13. 3)3) Nucleic acid synthesisNucleic acid synthesis
ex: quinolones(binds to bacterial complex of DNA & DNAex: quinolones(binds to bacterial complex of DNA & DNA
gyrase , blocking DNA replication ), Nitroimidazoles-gyrase , blocking DNA replication ), Nitroimidazoles-
metronidazole (strand breaking in the DNA), Rifampicinmetronidazole (strand breaking in the DNA), Rifampicin
(bind to DNA directed RNA Polymerase, block RNA(bind to DNA directed RNA Polymerase, block RNA
synthesis ), acyclovir (acyclovir triphosphate getssynthesis ), acyclovir (acyclovir triphosphate gets
incorporated in viral DNA and stops lengthening of DNAincorporated in viral DNA and stops lengthening of DNA
strand. The terminated DNA inhibits DNA-polymerasestrand. The terminated DNA inhibits DNA-polymerase
irreversibly)irreversibly)
4)4) Ribosomal functionRibosomal function
ex: Aminogycosides (binds to 30 s & 50s subunit of ribosome,ex: Aminogycosides (binds to 30 s & 50s subunit of ribosome,
causing misreading of genetic code), tetracyclines( bind tocausing misreading of genetic code), tetracyclines( bind to
30s, inhibit binding of aminoacyl-tRNA into A site of the30s, inhibit binding of aminoacyl-tRNA into A site of the
bacteria), chloramphenicol (bind to 50s,inhibit peptide bondbacteria), chloramphenicol (bind to 50s,inhibit peptide bond

14. Antimicrobials interfering with
ribosomal function : inhibition of
protein synthesis

15. 5)5) Folate synthesisFolate synthesis
ex: sulfonamides & trimethoprim, inhibitex: sulfonamides & trimethoprim, inhibit
synthesis of folate needed for synthesis ofsynthesis of folate needed for synthesis of
DNA , RNA & bacterial cell wall.DNA , RNA & bacterial cell wall.