Drug resistance occurs when microorganisms become unaffected or resistant to drugs like antimicrobials that were previously able to treat them. Resistance can be natural or acquired through mutations over time when exposed to drugs. It poses a major clinical problem. Many bacteria have become multidrug-resistant, including Staphylococcus aureus and Streptococcus pneumoniae. Resistance occurs through various mechanisms like drug inactivation, alteration of drug targets, or reducing drug accumulation in microbes. The spread of resistance is promoted through incomplete treatment courses and overuse of antibiotics. New drug development aims to overcome resistance mechanisms.

1. DRUG RESISTANCE
By Muhammed rashid ak
Medical college calicut

2.  Unresponsiveness of a microorganism to an
antimicrobial.
 Drug resistance is the reduction in
effectiveness of a drug such as an
antimicrobial or an antineoplastic in curing a
disease or condition.
 When an organism is resistant to more than
one drug, it is said to be multidrug-resistant.

3. • It took less than 20 years for, bacteria to show
signs of resistance.
• Staphylococcus aureus, which causes blood
poisoning and pneumonia, started to show
resistance in the 1950s.
• Today there are different strains of S. aureus
resistant to every form of antibiotic in use.

4. Natural resistance-
 some microbes are always been resistant to
certain AMA.
 They lack the metabolic process or the target
site which is affected by the particular drug.
 Species or group charecteristics.
 Eg:gram negative bacilli are normally.
unaffected by penicillin G,M.tuberculosis to
tetracycline's.
 Does not pose clinical problem.

6. Acquired Resistance
 Development of resistance by an organism
which was sensitive before ,due to the use of
an AMA over a peried of time.
 This can happen with any organism and is a
majour clinical problem.
 Devolopment of resistance is dependent on
the microorganism as well as the drug.
 Eg:
 Staphylococci,coliforms,tubercle bacilli-rapid
acquisition of resistance.

7. Mechanisms of drug resistance
 Drug inactivation or modification: e.g., enzymatic
deactivation of Penicillin G in some penicillin-resistant
bacteria through the production of β-lactamases.
 Alteration of target site: e.g., alteration of PBP— the
binding target site of penicillins — in MRSA and other
penicillin-resistant bacteria.
 Alteration of metabolic pathway: e.g., some sulfonamide-
resistant bacteria do not require (PABA), an important
precursor for the synthesis of folic acid and nucleic acids in
bacteria inhibited by sulfonamides. Instead, like
mammalian cells, they turn to utilizing preformed folic acid.

8. • Reduced drug accumulation: By decreasing
drug permeability and/or increasing active
efflux (pumping out) of the drugs across the
cell surface.

9. Antibiotics promote resistance
• If a patient does not complete course of antibiotic
Or forgets to take the doses regularly,
then resistant strains get a chance to build up.
• The antibiotics also kill innocent by standers
bacteria which are non-pathogens.
reduces the competition for the resistant
pathogens.
• The use of antibiotics also promotes antibiotic
resistance in non-pathogens too.
• These non-pathogens may later pass their
resistance genes on to pathogens .

10. Resistance gets around
• When antibiotics are used on a person, the
numbers of antibiotic resistant bacteria
increase in other members of the family.
• In places where antibiotics are used
extensively e.g. hospitals and farms
antibiotic resistant strains increase in numbers

11. Resistant pathogens
Staphylococcus aureus
•Major resistant pathogen.
•Found on the mucous membranes and the
human skin of around a third of the population.
extremely adaptable to antibiotic pressure.
•Community-acquired MRSA responsible for
rapidly progressive, fatal diseases, including
necrotizing pneumonia, severe sepsis and
necrotizing fasciitis. ,
•oxazolidinones, (oxazolidinone,
linezolid),vancomycin are the antibiotics used.

12. Streptococcus and Enterococcus
S. pneumonia is responsible for pneumonia,
bacteremia, otitis media, meningitis, sinusitis,
peritonitis and arthritis.
Resistance of Streptococcus pneumoniae to
penicillin and other beta-lactams is increasing
worldwide.

13. Pseudomonas aeruginosa
Clostridium difficile
Salmonella and e.coli

14. Resistance To β-lactam Antibiotics
•Act by inhibiting the carboxy or
transpeptidase or penicillin binding protiens in
peptidoglaycon synthesis.
•Resistance is caused by
•β-lactamase(most common)
•Mutation in the PBPs –reduced affinity
•Reduced uptake and efflux.

15. β-lactamases
•Catalyse the ring opening reaction of β-lactam
moity.
•Classified as classes A-D based on peptide
sequence.
•Class A,C,D have a serine at the active site.
•Class B have four zinc atoms at their active site.
So called-metallo β-lactamase.
•Class A-active against benzyl pencillin.
•Class B-effective against penicillins and
cephalosporins.
.

16. •Class C-Inducible,mutation lead to over
expression.
•Class D-composed of OXA type enzymes which
can hydrolyse oxacillin.
β-lactamase Inhibitors
Clavunalic acid,sulbactam
Altered PBP is responsible for resistance by
Streptococcus pneumoniae(PBP1a,PBP2b,PBP2x).
Haemophilus influenzae(PBP3A,PBP3b).

17. Resistance to Glycopeptide Antibiotic
•Vancomycine and teicoplanin.
•Bind the terminal D-alanine side chains of pepetidoglycan
and prevent cross linking in gram positive bacteria.
•Resistance to vancomycin is via a sensor histidine
kinase(vanS) and a response regulator (vanR).
•Van H encodes a D-lactate dehydrogenasealpha-keto
acid redutase and generates D-lactate ,which is the
substrate for VanA(D-Ala-D-Lac ligase).
•Cell wall precurser terminate at D-Ala-D-Lac to which
vancomycin bind with very low affinity.
•This change in affinity is mediated by one Hydrogen
bond.
•Selective pressure.

18. Resistance to Aminoglycoside Antibiotics
• Binding to the A site interferes with the accurate
recognition of cognate t-RNA during translation
and also perturb translocation of the t-RNA from
the active A-site to the peptidyl t-Rna site(p-site).
•High level resistance is due to methylation of r-
RNA(not in previously susceptible).
Mechanism in clinical aminoglycoside
resistance is their structural modification by the
enzymes in resistant organisms
•Aminoglycoside phosphatase(APHs)
•Aminoglycoside nucleotidyl transferase(ANTs)
•Aminoglycoside acetyl transferase(AACs)

19. Prevention
Structural modification.
Eg:tobramycin-lacks 3’-OH group and is not a
substrate for APH(3’)
Amikacin-has an acylated N-1 group and is not a
substrate.
3’-oxo kanamycin

20. Resistance to Tetracycline Antibiotics
•Resistant organisms are shigella
flexneri,salmonella enterica,serovour
typhimonium,MRSA,Streptococcus pneumoniae.
•Majour mechanism of resistance are efflux and
ribosomal protection.
• Tet efflux protien exchange a proton for a
tetracycline –Mg2+ complex reducing the
intracellular drug concentration and protecting
target ribosom.

21. Modifications
9-glycinyl tetracycline(9-glycylcyclines),9-
amino acylamido derivative minocycline,N,N-
dialkylamine or 9—t-butyl –glycylamido
moity.
Active against Tet gens.

22. Resistance to Flouroquinolone antibiotics
•Flouroquinolone bind and inhibit
DNA Gyrase(topoisomerase II)-DNA supercoiling
Topoisomerase 4-strand separation during cell
division.
•The A and B subunits of DNA gyrase are encoded
by gyrA,gyrB ,
•topoisomerase 4 encoded by ParC,parE.
•Mutation to the gyrA ,involving substitution of a
OH group with bulky hydrophobic group induce
conformational change –flouroquinolone cant
bind.

23. •Alteration involving ser80 and glut84 of
S.aureus grlA and seR79 ,Asp 83 of
s.pneumoniae par c led to quinoline resistance.
•Changes in outer membrane permiability(nor A
mediated efflux system ) –resistance in gram –
ve.

24. Resistance to Macrolide ,lincosamide and
streptogramine
•Inhibit bacterial protien synthesis by binding to
target site on mRNA.
•Gram –ve- intrinsically resistant due to
permiability barrier of the outer membrane.
3 mechanisms of resistance in gram +ve.
1.Target modification,involving adenine
methylation of domain-v of 23s ribosomal RNA.
The adenine –N6- methyl transferase encoded
by erm gene –resistance to erythromycine and
other macrolide,lincosamide and group B
streptogramins.

25. 2.Efflux-
Expression of mef gene-resistanes to
macrolide.
Expression of msr-resistance to macrolide and
streptoganins.
3.Ribosomal mutation-in small no of
s.pneumoniae.

26. Resistance to Peptide Antibiotics-polymyxin
Self promoted uptake across the cell envelop
and perturb the cytoplasmic membrane
barrier.
Addition of a 4-amino-4-deoxy-L-arabinose(L-
ara4N) moiety to the phosphate groups on the
lipid A component of gram -ve bacteria leads
to resistance.

27. Multiple drug resistance
• 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 (tumor) cells.

28. • Common MultiDrug-Resistant Organisms
(MDROs)
• Vancomycin-Resistant Enterococci (VRE)
• Methicillin-Resistant Staphylococcus aureus
(MRSA)
• Extended-spectrum ß-lactamse (ESBLs) producing
Gram-negative bacteria
• Klebsiella pneumoniae carbapenemase (KPC)
producing Gram-negatives
• Imipenem-resistant or MultiDrug-Resistant
Organisms Acinetobacter baumannii
• Imipenem-resistant or MultiDrug-Resistant
Organisms Pseudomonas aerginosa

29. Mechanisms in attaining multidrug resistance
• No longer relying on a glycoprotein cell wall.
• Enzymatic deactivation of antibiotics.
• Decreased cell wall permeability to antibiotics
• Altered target sites of antibiotic
• Efflux mechanisms to remove antibiotics.
• Increased mutation rate as a stress response.

30. R-Factors
Isolates become resistant to multiple ,chemically
distinct agents in a single biological event.
Eg:Previously sensitive E.coli become resistant to
multiple antibiotics through acqisition of a
conjugative plasmid called R Factor from resistant
salmonella and shigella isolates.
•Rp4-encoding resistance to ampicillin
,kanamycin,tetracyclin and neomycin found in
p.auriginosa and other gram –ves.
•R1-encoding resistance to ampicillin
,kanamycin,sulphonamides etc found in gram –ves
•PsH6

31. Mobile gene cassettes and Integrons
•Many gram –ve resistance genes are located
in gene cassettes.
•One or more of these cassettes are can be
integrated in to a specific position on the
chromosome termed as an integron.
•Integrons are genetic element that recognises
and capture multiple mobile gene cassettes.
•4 types of integrons are identified.

32. Chromosomal multiple antibiotic resistance(Mar)
locus
•First described in e.coli.
•Locus consists of two divergently transcribed units
,mar c and marAB.
•Increased expression of the marAB operon resulting
from mutations in marO or marR,or from
inactivation of marR following exposure to inducing
agents such as salicylate leads to marR phenotype.
•marR phenotype is characterised by resistance to
structuarally unrelated antibiotics,organic
solvents,oxidative stress and chemical disinfectants.

33. Neoplastic resistance
Main cause of failure in treatment of cancer.
Variety of factors like individual variation in
patients and somatic cell genetic differences in
tumour.
Intrinsic or aquired.
Reasons
•Most common reason is expression of one or
more energy dependent transporters that detects
and ejects anticancer drugs from cells.
•Insensitivity to drug induced apoptosis.
•Induction of drug detoxifying mechanisms

34. Reference
1.Text book of pharmaceutical biotechnology
hugo @russels
2.Pubmed