Antibiotic Resistance in Bacteria: Mbbs/Bds 1 Year 27.10.2010

Antibiotic resistance in Bacteria
MBBS/BDS 1st year

27.10.2010
Antibiotic resistance in bacteria
 Emergence of antibiotic resistance is a major factor
limiting long term successful use of an antimicrobial
agent.
 Antibiotic resistance is a type of drug resistance where a

microorganism is able to survive exposure to an antibiotic.
 Resistant organism: One that will not be inhibited or killed

by an antibacterial agent at concentrations of the drug
achievable in the body after normal dosage.
 If a bacterium carries several resistance genes, it is called

multiresistant or, informally, a superbug or super bacteria.
Factors contributing for resistance
 Misuse of antibiotics
< Use of antibiotics with no clinical indication (e.g, for viral
infections)
< Use of broad spectrum antibiotics when not indicated
< Inappropriate choice of empiric antibiotics
 Overuse of antibiotics
 Addition of antibiotic to the feed of livestock
 Failure to follow infection control practices

Settings that Foster Drug Resistance
Community
< Day-care centers
< Long term care facilities
< Homeless shelters
< Jails
Settings that Foster Drug Resistance
Hospital
< Intensive care units
< Oncology units
< Dialysis units
< Rehab units
< Transplant units
< Burn units
Antibiotic resistance in bacteria
 Two types:
Intrinsic:
 Naturally occuring trait
 Species or genus specific
Acquired:
 Acquired resistance implies that a susceptible organism has
developed resistance to an agent to which it was previously
susceptible, and can occur in two general ways: by mutation
(s) in the existing DNA of the organims or by acquisition of
new DNA.
 Present in only certain strains of a species or of a genus

Genetics of Resistance
Mutational resistance:
 A single chromosomal mutation may result in the
synthesis of an altered protein: for example,
streptomycin resistance via alteration in a ribosomal
protein, or the single aminoacid change in the enzyme
dihydtropteroate synthetase resulting in a lowered
affinity for sulfonamides
 A series of mutations, for example, changes in

penicillin binding proteins (PBPs) in penicillin resistant
pneumococci
Genetics of Resistance
 Resistance by acquisition of new DNA
– By Transformation
– Conjugation
– Transduction
Nature of elements involved in transferring DNA:

 Plasmids: plasmid mediated resistance much more efficient
than the resistance ass. with chromosomal mutation
 Transposons
Mechanism of action of antibiotics
DNA gyrase DNA-directed
RNA polymerase
Quinolones
Cell wall synthesis Rifampin
ß-lactams &
Glycopeptides
(Vancomycin) DNA
THFA mRNA
Trimethoprim Protein
Ribosomes synthesis
Folic acid inhibition
synthesis DHFA 50 50 50
30 30 30 Macrolides &
Lincomycins
Sulfonamides
PABA
Protein synthesis
Protein synthesis inhibition
mistranslation Tetracyclines
Aminoglycosides
Cohen. Science 1992; 257:1064
Mechanisms of antibiotic resistance : how DO
the bacteria do it ??
Mechanisms of resistance (Contd.)
2. Alteration of Access to the target site (altered uptake or increased exit)
Involves decreasing the amt of drug that reaches the target by either:
 Altering entry, for example, by decreasing the permeability of the cell wall,
 Pumping the drug out of the cell (known as efflux mechanisms)
3. Enzymatic inactivation:
Enzymes that modify or destroy the antibacterial agent may be produced

(drug inactivation)
e.g.,
Beta lactamases
Aminoglycoside modifying enzymes
Chloramphenicol acetyl transferase
4. Bypass of an antibiotic sensitive steps

Mechanisms of resistance:
Resistance mechanisms can be broadly
classified into 4 types:
1. Alteration of the target site

– The target site may be altered so that it has a
lowered affinity for the antibacterial (antibiotic),
but still functions adequately for nomal
metabolism to proceed. Alternatively, an
additional target (e.g enzyme) may be
synthesized.
Mechanism of resistance to particular
antibiotics
Resistance to β -lactams:
 Resistance due to β -lactamases: most prevalent
 Alteration in the pre-existing penicillin binding proteins

(PBPs)
 Acquisition of a novel PBP insensitive to beta β –

lactams: e.g, methicillin resistance in Staphylococcus
aureus (MRSA)
 Changes in the outer membrane proteins of Gram

negative organisms that prevent these compounds
from reaching their targets
Aminoglycoside Resistance:
Intrinsic and acquired resistance due to decreased

uptake
Acquired resistance is frequently due to plasmid

encoded modifying enzymes:
Three classes of aminoglycoside modifying enzymes:
 Acetyltransferases,
 Adenyltransferases and
 Phosphotransferases
Ribosomal target modification

Tetracycline resistance
Most common antibiotic resistance
encountered in nature
Mechanisms:
 Altered permeability due to chromosomal mutations
 Active efflux or Ribosomal protection (by
production of a protein) resulting from acquisition
of exogenous DNA
Macrolide, Lincosamide and
Streptogramin resistance:
 Intrinsic resistance is due to low permeability of

outermembrane protein
 Acquired resistance occurs most often by

alteration of the ribosomal target
 Drug inactivation and active efflux may also occur

Chloramphenicol resistance
 Enzymatic inactivation:
– From acquisition of plasmids encoding
chloramphenicol acetyl transferase
 Decreased permeability:
Quinolone resistance
 Alteration of target i.e, DNA gyrase (by
mutation in gyrA gene)
 Decreased permeability
Glycopeptide resistance
 Alteration of target
e.g, Vancomycin resistance in Enterococci
Cotrimoxazole (Sulfonamides and
trimethoprim) resistance
 Intrinsic resistance: outer membrane

impermeability
 Acquired resistance:
– Chromosomal mutations in the target enzymes
[low level resistance)
– Plasmid mediated resistance: high level resistance
Resistance to antimycobacaterial
agents
 First line essential antituberculous agents:
Rifampin, isoniazid and Pyrazinamide
 First line supplemental: Ethambutol and
Streptomycin
 Second line: Para-aminosalicylic acid,
ethionamide, cycloserine, kanamycin,
amikacin, capreomycin, thiacetazone
 Resistance to Rifampin:
– From spontaneous point mutations that alter the beta
subunit of the RNA polymerase (rpoB) gene
 Resistance to Isoniazid:
– Mutations in the catalase peroxidase gene or inhA
gene
 Resistance to Pyrazinamide:
– Mutations in the pncA gene, which encodes for
pyrazinamidase
Multidrug resistance/ XDR

Some resistant pathogens
Staphylococcus aureus:
 Penicillin resistance in 1947
 Methicillin resistance in 1961: MRSA causing carious
fatal diseases
 Vancomycin resistance in the recent years: As VRSA
and VISA
Enterococci:
 Penicillin resistance seen in 1983
 Vancomycin resistant Enterococcus (VRE) in 1987
 Even emergence of linezolid resistance
Some resistant pathogens (contd.)
 Pseudomonas aeruginosa:
– One of the worrisome characteristic: low antibiotic
susceptibility
– Multidrug resistance common: due to mutation or
horizontal transfer of resitant genes
 Acinetobacter baumanii
 Multidrug resistance
 Some isolates resistant to all drugs
 Salmonella, Esherichia coli
 Mycobacterium tuberculosis
Tests for detecting antibacterial resistance
 Disk diffusion method
 Screening method: eg, oxacillin resistance screening

for Staphylococcus, Vancomycin resitance screeening
for enterococci
 Agar dilution method: by determining minimum

inhibitory concentration
 Special tests: detection of enzymes mediating

resistance- colorometric nitrocefin and acidometric
method for beta lactamase detection
Limitation of Drug Resistance
Emergence of drug resistance in infections may be minimized in the
following ways:
 By prudent use of antibiotics; by avoiding exposure of
microorganisms to a particularly valuable drug by limiting its use,
especially in hospitals.
 By maintaining sufficiently high levels of the drug in the tissues to

inhibit both the original population and first-step mutants;
 By simultaneously administering two drugs that do not give cross-

resistance, each of which delays the emergence of mutants
resistant to the other drug (eg, rifampin and isoniazid in the
treatment of tuberculosis); and
 By institution of infection control practices

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Antibiotic resistance in Bacteria

MBBS/BDS 1st year

 Antibiotic resistance is a type of drug resistance where a

 Resistant organism: One that will not be inhibited or killed

 If a bacterium carries several resistance genes, it is called

 Addition of antibiotic to the feed of livestock

 Failure to follow infection control practices

< Long term care facilities

< Homeless shelters

 Present in only certain strains of a species or of a genus

 A series of mutations, for example, changes in

Nature of elements involved in transferring DNA:

Enzymes that modify or destroy the antibacterial agent may be produced

4. Bypass of an antibiotic sensitive steps

1. Alteration of the target site

 Resistance due to β -lactamases: most prevalent

 Alteration in the pre-existing penicillin binding proteins

 Acquisition of a novel PBP insensitive to beta β –

 Changes in the outer membrane proteins of Gram

Intrinsic and acquired resistance due to decreased

Acquired resistance is frequently due to plasmid

Ribosomal target modification

 Intrinsic resistance is due to low permeability of

 Acquired resistance occurs most often by

 Drug inactivation and active efflux may also occur

 Intrinsic resistance: outer membrane

Multidrug resistance/ XDR

 Salmonella, Esherichia coli

 Disk diffusion method

 Screening method: eg, oxacillin resistance screening

 Agar dilution method: by determining minimum

 Special tests: detection of enzymes mediating

 By maintaining sufficiently high levels of the drug in the tissues to

 By simultaneously administering two drugs that do not give cross-

 By institution of infection control practices

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