Dr. Manal El Said

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Antimicrobial Drugs Mechanism of Action
Dr. Manal El Said
Department Head of Microbiology
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Antimicrobial Drugs Resistance

• Four main mechanisms of antibiotic resistance
  are
• (1) enzymatic degradation of drug
• (2) modification of drug's target
• (3) reduced permeability of drug
• (4) active export of drug.
• Most drug resistance is result of genetic change
  in organism, caused either by chromosomal
  mutation or acquisition of plasmid or transposon.

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Antimicrobial Drugs Major Mechanisms of
Bacterial Resistance
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Antimicrobial Drugs Major Mechanisms of
Bacterial Resistance
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Antimicrobial Drugs Resistance Specific
Mechanisms of Resistance
Bacterial resistance to antibioticsproducing an
enzyme to destroy or inactivate the antibiotic.
This animation can be found at The Grapes of
Staph Doc Kaiser's Microbiology Website,
http//student.ccbcmd.edu/gkaiser/goshp.html.
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Antimicrobial Drugs Resistance Specific
Mechanisms of Resistance
Bacterial resistance to antibioticsproducing an
altered enzyme to which the antibiotic no longer
binds. This animation can be found at The Grapes
of Staph Doc Kaiser's Microbiology Website,
http//student.ccbcmd.edu/gkaiser/goshp.html.
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Antimicrobial Drugs Resistance Specific
Mechanisms of Resistance
Bacterial resistance to antibioticsproducing an
altered ribosomal subunit to which the antibiotic
no longer binds. This animation can be found at
The Grapes of Staph Doc Kaiser's Microbiology
Website, http//student.ccbcmd.edu/gkaiser/goshp.
html.
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Antimicrobial Drugs Resistance Specific
Mechanisms of Resistance
A bacterium producing altered porins that block
passage of the antibiotic through the outer
membrane of a gram-negative bacterium.
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Antimicrobial Drugs Resistance Specific
Mechanisms of Resistance
A bacterium producing an altered transport
(carrier) protein that prevents transport of the
antibiotic through the cytoplasmic membrane.
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Antimicrobial Drugs Resistance Specific
Mechanisms of Resistance
A bacterium producing transporter molecules that
pump the antibiotic out of the bacterium.
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Antimicrobial Drugs Resistance Specific
Mechanisms of Resistance
A bacterium producing greater amounts of the
limited enzyme being tied up or inactivated by
the antimicrobial agent. Although some enzyme is
tied up by the drug, there is still enzyme
available to react with its substrate and produce
end products.
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Antimicrobial Drugs Resistance Genetic Basis of
Resistance

• Chromosomal mutations typically
• -Change target of drug so that drug does not
  bind
• -Change membrane so that drug does not
  penetrate well into cell.
• Chromosomal mutations occur at low frequency
  (perhaps 1 in 10 million organisms).
• It often affect only one drug or one family of
  drugs.

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Antimicrobial Drugs Resistance Genetic Basis of
Resistance

• Plasmids cause drug resistance by encoding
  enzymes that degrade or modify drugs.
• Plasmid-mediated resistance occurs at higher
  frequency, often affecting multiple drugs or
  families of drugs.
• Resistance plasmids (R plasmids, R factors) carry
  two sets of genes
• - One set encodes enzymes that degrade or
  modify drugs
• - Other encodes proteins that mediate
  conjugation

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Antimicrobial Drugs Resistance Genetic Basis of
Resistance

• Transposons are small pieces of DNA that move
• - from one site on bacterial chromosome to
  another or,
• - from bacterial chromosome to plasmid DNA.
  
• Transposons often carry drug resistance genes.
• Many R plasmids carry one or more transposons.

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Antimicrobial Drugs Resistance Genetic Basis of
Resistance
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Antimicrobial Drugs Resistance Specific
Mechanisms of Resistance

• Resistance to penicillins cephalosporins is
  mediated by three main mechanisms
• (1) degradation by ß-lactamases (most
  important)
• (2) mutations in genes for penicillin-binding
  proteins
• (3) reduced permeability.

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Antimicrobial Drugs Resistance Specific
Mechanisms of Resistance
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Antimicrobial Drugs Resistance Specific
Mechanisms of Resistance

• Resistance to vancomycin is caused by change in
  D-alanyl-D-alanine part of peptide in
  peptidoglycan to D-alanine-D-lactate, resulting
  in inability of vancomycin to bind.

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Antimicrobial Drugs Resistance Specific
Mechanisms of Resistance

• Resistance to aminoglycosides is mediated by
  three main mechanisms
• modification of drug by phosphorylating,
  adenylylating, acetylating enzymes
• mutations in genes encoding one of 30S ribosomal
  proteins
• reduced permeability.

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Antimicrobial Drugs Resistance Specific
Mechanisms of Resistance
Resistance to tetracyclines is caused by either
- reduced permeability - active export of
drug from bacterium.
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Antimicrobial Drugs Resistance Specific
Mechanisms of Resistance
Resistance to erythromycins is caused by
plasmid-encoded enzyme that methylates 23S
ribosomal RNA, thereby blocking binding of the
drug.
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Antimicrobial Drugs Resistance Specific
Mechanisms of Resistance
Resistance to sulfonamides is due to
plasmid-encoded enzymes that actively export drug
from bacterium.
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Antimicrobial Drugs Resistance Specific
Mechanisms of Resistance
Resistance to quinolones is caused by mutations
in gene encoding bacterial DNA gyrase.
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Antimicrobial Drugs Resistance Specific
Mechanisms of Resistance
Resistance to rifampin is caused by mutations in
gene encoding bacterial RNA polymerase.
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Antimicrobial Drugs Resistance Specific
Mechanisms of Resistance
Resistance to isoniazid is due to loss of
bacterial peroxidase (catalase) that activates
isoniazid to metabolite that inhibits mycolic
acid synthesis.
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Antimicrobial Drugs Nongenetic Basis of
Resistance

• Drugs may not reach bacteria located in center of
  abscess
• Certain drugs, such as penicillins, will not
  affect bacteria that are not growing.
• Presence of foreign bodies makes successful
  antibiotic treatment more difficult.

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Antimicrobial Drugs Antibiotic Sensitivity
Testing
The minimal inhibitory concentration (MIC) It is
lowest concentration of drug that inhibits growth
of bacteria isolated from patient (it is not
known whether inhibited bacteria have been killed
or just have stopped growing). The minimal
bactericidal concentration (MBC) It is lowest
concentration of drug that kills bacteria
isolated from patient.
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Antimicrobial Drugs Use of Antibiotic
Combinations

• Two or more antibiotics are used to
• - treat life-threatening infections before
  cause has been identified,
• - prevent emergence of resistant bacteria
  during prolonged treatment regimens
• - achieve synergistic (augmented) effect.

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Antimicrobial Drugs Use of Antibiotic
Combinations

• Synergistic effect is one in which effect of two
  drugs given together is much greater than sum of
  effect of two drugs given individually.
• Example of synergy is marked killing effect of
  combination of penicillin aminoglycoside on
  enterococci compared to minor effect of either
  drug given alone.

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Antimicrobial Drugs Use of Antibiotic
Combinations
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Bacterial Vaccines

• Immunity to certain bacterial diseases can be
  induced by
• Immunization with bacterial antigens (active
  immunity)
• Administration of preformed antibodies (passive
  immunity).

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Active Immunity

• Active immunity can be achieved by vaccines
  consisting of
• bacterial capsular polysaccharides, toxoids,
  whole bacteria (either killed or live,
  attenuated)
• purified proteins isolated from bacteria.

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Active Immunity

• Vaccines containing capsular polysaccharide as
  immunogen are directed against
• Streptococcus pneumoniae
• Haemophilus influenzae
• Neisseria meningitidis
• Salmonella typhi.

Capsular polysaccharide is conjugated to carrier
protein to enhance antibody response.
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Active Immunity

• Two vaccines contain toxoids as immunogen
• - Diphtheria
• - Tetanus.
• Toxoid is inactivated toxin that has lost its
  ability to cause disease but has retained its
  immunogenicity.

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Active Immunity

• Two vaccines contain purified bacterial proteins
  as immunogen
• Acellular pertussis vaccine combination with
  diphtheria tetanus toxoids
• It is recommended for all children.
• Anthrax vaccine contains purified proteins
• It is recommended only for individuals who are
  likely to be exposed to organism.

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Active Immunity

• BCG vaccine against tuberculosis contains live,
  attenuated Mycobacterium bovis is used in
  countries where the disease is endemic.
• One of vaccines against typhoid fever contains
  live, attenuated Sal. typhi.
• Vaccines against cholera, plague, typhus, Q
  fever contain whole killed bacteria.
• These vaccines are used only to protect those
  likely to be exposed.

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Passive Immunity

• Passive Immunity
• Antitoxins for prevention treatment of
• - Tetanus
• - Botulism
• - Diphtheria.
• These three diseases are caused by exotoxins.
• Antitoxins (antibodies against exotoxins) bind to
  exotoxins prevent their toxic effects, i.e.,
  they neutralize toxins.

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PassiveActive Immunity

• This involves providing both immediate (but
  short-term) protection in form of antibodies
  long-term protection in form of active
  immunization.
• Example of use of passive-active immunity is
  prevention of tetanus in unimmunized person who
  has sustained contaminated wound.
• Both tetanus antitoxin tetanus toxoid should be
  given.
• They should be given at different sites so that
  antibodies in antitoxin do not neutralize toxoid.

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Recommended Immunization Schedule
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Recommended Immunization Schedule
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Recommended Immunization Schedule