Transcript Antimicrobial Drugs: Mechanism of Action

Batterjee Medical College
Batterjee Medical College
Antimicrobial Drugs:
Mechanism of Action
Dr. Manal El Said
Head of Microbiology Department
Batterjee Medical College
Antimicrobial Drugs: Mechanism of
Action: Introduction
• There are four major sites in bacterial cell that serve as
basis for action of effective drugs:
1.Cell wall
2. Ribosomes
3. Nucleic acids
4. Cell membrane
Batterjee Medical College
Antimicrobial Drugs: Mechanism of
Action: Introduction
Batterjee Medical College
Antimicrobial Drugs: Mechanism of
Action: Introduction
Mechanism of Action
Drugs
Inhibition of cell wall synthesis
Inhibition of cross-linking (transpeptidation) -Penicillins
of peptidoglycan
-Cephalosporins
- Imipenem
- Aztreonam,
- Vancomycin
Inhibition of other steps in peptidoglycan
- Cycloserine
synthesis
- Bacitracin
Antifungal activity inhibition of β-glucan
- Caspofungin
synthesis
Inhibition of protein synthesis
Action on 50S ribosomal subunit
- Chloramphenicol
- erythromycin
- clindamycin
- linezolid
Action on 30S ribosomal subunit
-Tetracyclines
- Aminoglycosides
Batterjee Medical College
Antimicrobial Drugs: Mechanism of
Action: Introduction
Mechanism of Action of Important Antibacterial and Antifungal Drugs
Drugs
Mechanism of Action
Inhibition of nucleic acid synthesis
Inhibition of nucleotide synthesis
Sulfonamides, trimethoprim
Inhibition of DNA synthesis
Quinolones, e.g., ciprofloxacin
Inhibition of mRNA synthesis
Rifampin
Alteration of cell membrane function
Antibacterial activity
Antifungal activity
Polymyxin, daptomycin
Amphotericin B, nystatin,
terbinafine, azoles, e.g.,
itraconazole
Other mechanisms of action
1. Antibacterial activity
2. Antifungal activity
Isoniazid, metronidazole,
ethambutol, pyrazinamide
Griseofulvin, pentamidine
Batterjee Medical College
Antimicrobial Drugs: Mechanism of
Action: Introduction
Selective toxicity
• It is selective inhibition of growth of microorganism without
damage to host.
• It is achieved by exploiting differences between metabolism
& structure of microorganism & human cells.
• Penicillins & cephalosporins are effective antibacterial
agents
prevent synthesis of peptidoglycan
inhibiting growth of bacterial (not human cells).
Batterjee Medical College
Antimicrobial Drugs: Mechanism of
Action: Introduction
Broad-spectrum antibiotics
• Broad-spectrum antibiotics are active against several types
of microorganisms
e.g., tetracyclines are active against many gram-negative
rods, chlamydiae, mycoplasmas, & rickettsiae.
Narrow-spectrum antibiotics
• Narrow-spectrum antibiotics are active against one or very
few types,
e.g., vancomycin is used against certain gram-positive
cocci, staphylococci & enterococci.
Batterjee Medical College
Antimicrobial Drugs: Mechanism of
Action: Introduction
Bactericidal drug
• Bactericidal drug kills bacteria
Bacteriostatic drug
• Bacteriostatic drug inhibits their growth but does not kill
them
- Bacteria can grow again when drug is withdrawn
- Host defense mechanisms, such as phagocytosis, are
required to kill bacteria.
Batterjee Medical College
Antimicrobial Drugs: Mechanism of
Action: Introduction
Batterjee Medical College
Antimicrobial Drugs
Chemoprophylaxis
• Antimicrobial drugs are used to prevent infectious diseases
as well as to treat them.
• They are given primarily in three circumstances:
1. to prevent surgical wound infections
2. to prevent opportunistic
compromised patients
infections
in
immuno-
3. to prevent infections in those known to be exposed to
pathogens that cause serious infectious diseases.
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Antimicrobial Drugs:
Probiotics
• In contrast to chemical antibiotics, probiotics are live,
nonpathogenic bacteria that may be effective in treatment or
prevention of certain human diseases.
• The suggested basis for possible beneficial effect lies in:
1. providing colonization resistance by which nonpathogen
excludes pathogen from binding sites on mucosa
2. enhancing immune response against pathogen
3. reducing inflammatory response against pathogen.
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Antimicrobial Drugs:
Probiotics
• Oral administration of live Lactobacillus rhamnosus strain
GG significantly reduces number of cases of nosocomial
diarrhea in young children.
• Yeast Saccharomyces boulardii reduces risk of antibioticassociated diarrhea caused by Clostridium difficile.
• Adverse effects are few; however, serious complications
have arisen in highly immunosuppressed patients and in
patients with indwelling vascular catheters.
Batterjee Medical College
Antimicrobial Drugs:
Probiotics
Batterjee Medical College
Antimicrobial Drugs:
Probiotics
Batterjee Medical College
Antimicrobial Drugs:
Mechanism of Action
Dr. Manal El Said
Head of Microbiology Department
Batterjee Medical College
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
- Acquisition of plasmid or transposon.
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Antimicrobial Drugs:
Major Mechanisms of Bacterial Resistance
Batterjee Medical College
Antimicrobial Drugs:
Resistance: Specific Mechanisms of Resistance
Enzyme destroy or inactivate antibiotic
Bacterial resistance to antibiotics—producing 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.
Batterjee Medical College
Antimicrobial Drugs:
Resistance: Specific Mechanisms of Resistance
Altered Enzyme
Bacterial resistance to antibiotics—producing 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.
Batterjee Medical College
Antimicrobial Drugs:
Resistance: Specific Mechanisms of Resistance
Altered ribosomal subunit
Bacterial resistance to antibiotics—producing 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.
Batterjee Medical College
Antimicrobial Drugs:
Resistance: Specific Mechanisms of Resistance
Altered porins block passage of antibiotic
A bacterium producing altered porins that block passage of the antibiotic through the outer membrane of
a gram-negative bacterium.
Batterjee Medical College
Antimicrobial Drugs:
Resistance: Specific Mechanisms of Resistance
Altered transport (carrier) protein
A bacterium producing an altered transport (carrier) protein that prevents transport of the antibiotic through the
cytoplasmic membrane.
Batterjee Medical College
Antimicrobial Drugs:
Resistance: Specific Mechanisms of Resistance
Transporter molecules
A bacterium producing transporter molecules that pump the antibiotic out of the bacterium.
Batterjee Medical College
Antimicrobial Drugs:
Resistance: Specific Mechanisms of Resistance
Greater amounts of the limited enzyme
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.
Batterjee Medical College
Antimicrobial Drugs:
Resistance: Genetic Basis of Resistance
Chromosomal mutations
• Chromosomal mutations typically:
- Change target of drug
- Change membrane
drug does not bind
drug does not penetrate into cell.
• It occurs at low frequency (1 in 10 million organisms).
• It affect only one drug or one family of drugs.
Batterjee Medical College
Antimicrobial Drugs:
Resistance: Genetic Basis of Resistance
Plasmids
• Plasmids encoding enzymes that degrade or modify
drugs.
• It occurs at higher frequency
• it affects 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
Batterjee Medical College
Antimicrobial Drugs:
Resistance: Genetic Basis of Resistance
Transposons
• 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.
Batterjee Medical College
Antimicrobial Drugs:
Resistance: Genetic Basis of Resistance
Batterjee Medical College
Antimicrobial Drugs:
Nongenetic Basis of Resistance
Nongenetic Basis of Resistance
1. Drugs may not reach bacteria located in center of
abscess
2. Certain drugs, such as penicillins, will not affect bacteria
that are not growing.
3. Presence of foreign bodies makes antibiotic treatment
difficult.
Batterjee Medical College
Antimicrobial Drugs
Selection of Resistant Bacteria by Overuse & Misuse
of Antibiotics
• Overuse & misuse of antibiotics increase the occurrence of
gram-negative rods resistant to multiple antibiotics by
enhancing selection of resistant mutants:
1. Some physicians :
-Use multiple antibiotics when one would be sufficient
-Prescribe unnecessarily long courses of antibiotic therapy
-Use antibiotics in self-limited infections.
-Overuse antibiotics for prophylaxis before & after surgery.
Batterjee Medical College
Antimicrobial Drugs
Selection of Resistant Bacteria by Overuse & Misuse
of Antibiotics
2. In many countries, antibiotics are sold over the counter
to general public
encourages inappropriate &
indiscriminate use of the drugs.
3. Antibiotics are used in animal feed to prevent infections
and promote growth
in animals
in humans.
selects for resistant organisms
contribute to pool of resistant organisms
Batterjee Medical College
Antimicrobial Drugs:
Antibiotic Sensitivity Testing
The minimal inhibitory concentration (MIC)
It is lowest concentration of drug that inhibits growth of
bacteria isolated from patient
NB: 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.
Batterjee Medical College
Antimicrobial Drugs:
Use of Antibiotic Combinations
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.
Batterjee Medical College
Antimicrobial Drugs:
Use of Antibiotic Combinations
Use of Antibiotic Combinations
Synergistic
• Synergistic effect is : effect of two drugs
given together is much greater than sum of
effect of two drugs given individually.
e.g. marked killing effect of combination of
penicillin & aminoglycoside on enterococci
compared to minor effect of either drug
given alone.
Batterjee Medical College
Antimicrobial Drugs:
Use of Antibiotic Combinations
Rarely, the effect of the two drugs together is antagonistic, in which the result is significantly lower
activity than the sum of the activities of the two drugs alone.
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Antimicrobial Drugs
Batterjee Medical College
Bacterial Vaccines
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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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Bacterial Vaccines
Active immunity
Active immunity can be achieved by vaccines consisting of:
(1) bacterial
capsular
polysaccharides,
bacteria (either killed or live, attenuated)
(2) purified proteins isolated from bacteria.
toxoids,
whole
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Bacterial Vaccines
Active immunity
Batterjee Medical College
Bacterial Vaccines
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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Bacterial Vaccines
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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Bacterial Vaccines
Active immunity
Two vaccines
immunogen:
contain
purified
bacterial
proteins
as
1-Acellular pertussis vaccine:
• Combination with diphtheria & tetanus toxoids
• It is recommended for all children.
2-Anthrax vaccine:
• Contains purified proteins
• It is recommended only for individuals who are likely to be
exposed to organism.
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Bacterial Vaccines
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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Bacterial Vaccines
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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Bacterial Vaccines
Passive–Active Immunity
• This involves providing both immediate (but short-term)
protection in form of antibodies & long-term protection in
form of active immunization.
• e.g. 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.