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بسم الله الرحمن الرحيم. Antimicrobial Drugs: Mechanism of Action. Dr. Manal El Said. Department Head of Microbiology. Antimicrobial Drugs: Mechanism of Action: Introduction. There are four major sites in bacterial cell that serve as basis for action of effective drugs: Cell wall - PowerPoint PPT Presentation
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Batterjee Medical College
Dr. Manal El SaidDr. Manal El Said Department Head of Microbiology
Antimicrobial Drugs: Mechanism of Action
Batterjee Medical College
• 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
Antimicrobial Drugs: Mechanism of Action: Introduction
Batterjee Medical College
Mechanism of Action DrugsInhibition of cell wall synthesisInhibition of cross-linking (transpeptidation) of peptidoglycan
-Penicillins-Cephalosporins- Imipenem- Aztreonam,- Vancomycin
Inhibition of other steps in peptidoglycan synthesis
- Cycloserine - Bacitracin
Antifungal activity inhibition of β-glucan synthesis
-Caspofungin
Inhibition of protein synthesisAction on 50S ribosomal subunit - Chloramphenicol
- erythromycin- clindamycin- linezolid
Action on 30S ribosomal subunit -Tetracyclines -Aminoglycosides
Antimicrobial Drugs: Mechanism of Action: Introduction
Batterjee Medical College
Mechanism of Action of Important Antibacterial and Antifungal Drugs
Mechanism of ActionDrugs
Inhibition of nucleic acid synthesis
Inhibition of nucleotide synthesisSulfonamides, trimethoprim
Inhibition of DNA synthesisQuinolones, e.g., ciprofloxacin
Inhibition of mRNA synthesisRifampin
Alteration of cell membrane function
Antibacterial activityPolymyxin, daptomycin
Antifungal activityAmphotericin B, nystatin, terbinafine, azoles, e.g., itraconazole
Other mechanisms of action
1 .Antibacterial activityIsoniazid, metronidazole, ethambutol, pyrazinamide
2 .Antifungal activityGriseofulvin, pentamidine
Antimicrobial Drugs: Mechanism of Action: Introduction
Batterjee Medical College
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.
Antimicrobial Drugs: Mechanism of Action: Introduction
• Penicillins & cephalosporins are effective antibacterial
agents prevent synthesis of peptidoglycan
inhibiting growth of bacterial (not human cells).
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• 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 are active against one or very
few types,
e.g., vancomycin is used against certain gram-positive
cocci, staphylococci & enterococci.
Antimicrobial Drugs: Mechanism of Action: Introduction
Batterjee Medical College
• Bactericidal drug kills bacteria
• 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.
Antimicrobial Drugs: Mechanism of Action: Introduction
Batterjee Medical College
• Bactericidal drugs are useful in certain infections:
1. Life-threatening
2. Patients whose polymorphonuclear leukocyte count is
below 500/μL
3.Endocarditis, in which phagocytosis is limited by fibrinous
network of vegetations & bacteriostatic drugs do not effect
cure.
Antimicrobial Drugs: Mechanism of Action: Introduction
Batterjee Medical College
• Penicillins & cephalosporins act by inhibiting
transpeptidases (penicillin-binding proteins, PBP)
enzymes that cross-link peptidoglycan.
• Several important bacteria, e.g., Streptococcus
pneumoniae, manifest resistance to penicillins based on
mutations in genes encoding PBP.
Antimicrobial Drugs: Mechanism of Action: Inhibition of Cell Wall Synthesis
Penicillins
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Antimicrobial Drugs: Mechanism of Action: Inhibition of Cell Wall Synthesis
Penicillins
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Antimicrobial Drugs: Mechanism of Action: Inhibition of Cell Wall Synthesis
Penicillins
Gram-negative Gram-positive
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mecA Gene & Production of Altered Penicillin Binding Protein. Altered penicillin binding protein (PBP2a) resists binding of beta-lactam antimicrobial, but maintains function of cross-lining bacterial cell wall components. Abbreviations: PBP = penicillin binding protein; SCC = staphylococcal chromosomal cassette
Antimicrobial Drugs: Mechanism of Action: Inhibition of Cell Wall Synthesis
Role of Penicillin Binding Protein in Cross-Linking of Bacterial Cell Wall Subunits
Penicillins
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• Exposure to penicillins activates autolytic enzymes
degrade bacteria.
• If these autolytic enzyme are not activated, e.g., in certain
strains of Staphylococcus aureus, bacteria are not killed &
strain is said to be tolerant.
Penicillins
Antimicrobial Drugs: Mechanism of Action: Inhibition of Cell Wall Synthesis
Batterjee Medical College
Penicillins
Antimicrobial Drugs: Mechanism of Action: Inhibition of Cell Wall Synthesis
Batterjee Medical College
• Penicillins kill bacteria when they are growing more
active during log phase of bacterial growth.
• Penicillins & cephalosporins are β -lactam drugs, i.e., intact
β -lactam ring is required for activity.
• β –lactamases (penicillinases & cephalosporinases) cleave β
-lactam ring & inactivate drug.
Penicillins
Antimicrobial Drugs: Mechanism of Action: Inhibition of Cell Wall Synthesis
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• Modification of side chain adjacent to β -lactam ring endows
these drugs with new properties:
- Expanded activity against gram-negative rods
- Ability to be taken orally
- Protection against degradation by β-lactamases.
Penicillins
Antimicrobial Drugs: Mechanism of Action: Inhibition of Cell Wall Synthesis
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• Penicillin G is available in three main forms:
1.Aqueous penicillin G (metabolized most rapidly).
2.Procaine penicillin G (penicillin G is conjugated to
procaine) & metabolized more slowly & is less painful when
injected intramuscularly (procaine acts as anesthetic).
3.Benzathine penicillin G (penicillin G is conjugated to
benzathine) & metabolized very slowly .
Penicillins
Antimicrobial Drugs: Mechanism of Action: Inhibition of Cell Wall Synthesis
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Benzylpenicillin has three disadvantages have been
overcome by chemical modification of side chain.
(1)Limited effectiveness against many gram-negative rods
(due to inability of drug to penetrate outer membrane of
organism)
(2)Hydrolysis by gastric acids & not be taken orally
Hydrolysis is prevented addition of oxygen (penicillin
V) or amino group (ampicillin)
As activity against gram-negative bacteria increases, activity against gram-positive bacteria decreases.
Penicillins
Antimicrobial Drugs: Mechanism of Action: Inhibition of Cell Wall Synthesis
Batterjee Medical College
Penicillins
Antimicrobial Drugs: Mechanism of Action: Inhibition of Cell Wall Synthesis
Batterjee Medical College
3) inactivation by β-lactamases. It can be blocked by:
-Modification of side chain with addition of large aromatic
rings containing bulky methyl or ethyl groups (methicillin,
oxacillin, nafcillin).
-Inhibitors such as clavulanic acid & sulbactam (structural
analogues of penicillin that have little antibacterial activity
but bind strongly to β-lactamases & protect penicillin).
Penicillins
Antimicrobial Drugs: Mechanism of Action: Inhibition of Cell Wall Synthesis
Batterjee Medical College
Penicillins
Antimicrobial Drugs: Mechanism of Action: Inhibition of Cell Wall Synthesis
methicillin
nafcillin
oxacillin
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• Cephalosporins have six-membered ring adjacent to β-
lactam ring & are substituted in two places on 7-
aminocephalosporanic acid nucleus (penicillins have five-
membered ring & are substituted in only one place).
• First-generation cephalosporins are active against gram-
positive cocci
• Second, third, & fourth generations have expanded
coverage against gram-negative rods.
Cephalosporins
Antimicrobial Drugs: Mechanism of Action: Inhibition of Cell Wall Synthesis
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Cephalosporins
Antimicrobial Drugs: Mechanism of Action: Inhibition of Cell Wall Synthesis
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Carbapenems
• Carbapenems are β-lactam drugs that has different
structure from penicillins & cephalosporins.
• Imipenem has widest spectrum of activity & excellent
bactericidal activity against :
-Gram-positive
-Gram-negative (including extended-spectrum β-
Lactamases resistant to all penicillins & cephalosporins)
- Anaerobic bacteria
Antimicrobial Drugs: Mechanism of Action: Inhibition of Cell Wall Synthesis
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Carbapenems
Antimicrobial Drugs: Mechanism of Action: Inhibition of Cell Wall Synthesis
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Carbapenems
• Imipenem is prescribed in combination with cilastatin,
which is inhibitor of dehydropeptidase, kidney enzyme
that inactivates imipenem.
• Imipenem is not inactivated by most β-lactamases
(carbapenemases have emerged).
• Two other carbapenems, ertapenem & meropenem, are
available.
Antimicrobial Drugs: Mechanism of Action: Inhibition of Cell Wall Synthesis
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• Vancomycin is glycopeptide, i.e., it is not β-lactam drug
• its mode of action is very similar to that of penicillins &
cephalosporins, i.e., it inhibits transpeptidases.
Antimicrobial Drugs: Mechanism of Action: Inhibition of Cell Wall Synthesis
Vancomycin
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Antimicrobial Drugs: Mechanism of Action: Inhibition of Cell Wall Synthesis
Vancomycin
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• Caspofungin is lipopeptide that inhibits fungal cell wall
synthesis by blocking synthesis of β-glucan,
polysaccharide component of cell wall.
Antimicrobial Drugs: Mechanism of Action: Inhibition of Cell Wall Synthesis
Caspofungin
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Antimicrobial Drugs: Mechanism of Action: Inhibition of Protein Synthesis
• Antibiotics act at level of 30S ribosomal subunit:
- Aminoglycosides
- Tetracyclines
• Antibiotics act at level of 50S ribosomal subunit:
- Chloramphenicol
- erythromycins
- clindamycin
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• Aminoglycosides inhibit bacterial protein synthesis by
binding to 30S subunit, which blocks initiation complex.
• No peptide bonds are formed & no polysomes are made.
• Aminoglycosides are family of drugs that includes:
- gentamicin
- tobramycin
- streptomycin
Antimicrobial Drugs: Mechanism of Action: Inhibition of Protein Synthesis
30S ribosomal subunit :Aminoglycosides
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Antimicrobial Drugs: Mechanism of Action: Inhibition of Protein Synthesis
30S ribosomal subunit :Aminoglycosides
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• Tetracyclines inhibit bacterial protein synthesis by
blocking binding of aminoacyl t-RNA to 30S ribosomal
subunit.
• Tetracyclines are family of drugs; doxycycline is used
most often.
Antimicrobial Drugs: Mechanism of Action: Inhibition of Protein Synthesis
30S ribosomal subunit :Tetracyclines
Batterjee Medical College
Antimicrobial Drugs: Mechanism of Action: Inhibition of Protein Synthesis
30S ribosomal subunit :Tetracyclines
Batterjee Medical College
Antimicrobial Drugs: Mechanism of Action: Inhibition of Protein Synthesis
30S ribosomal subunit :Tetracyclines
The tetracyclines (tetracycline, doxycycline, demeclocycline, minocycline )block bacterial translation by binding reversibly to the 30S subunit and distorting it in such a way that the anticodons of the charged tRNAs cannot align properly with the codons of the mRNA.
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• Chloramphenicol inhibits bacterial protein synthesis by
blocking peptidyl transferase, enzyme that adds new amino
acid to growing polypeptide.
• Chloramphenicol can cause bone marrow suppression.
Antimicrobial Drugs: Mechanism of Action: Inhibition of Protein Synthesis
50S ribosomal subunit: Chloramphenicol
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• Erythromycin inhibits bacterial protein synthesis by
blocking release of t-RNA after it has delivered its amino
acid to growing polypeptide.
• Erythromycin is member of macrolide family of drugs that
includes azithromycin & clarithromycin.
Antimicrobial Drugs: Mechanism of Action: Inhibition of Protein Synthesis
50S ribosomal subunit: Erythromycin
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• Clindamycin binds to same site on ribosome as does
erythromycin & is thought to act in same manner.
• It is effective against many anaerobic bacteria.
• Clindamycin is one of antibiotics that predisposes to
pseudomembranous colitis caused by Clostridium difficile &
is infrequently used.
Antimicrobial Drugs: Mechanism of Action: Inhibition of Protein Synthesis
50S ribosomal subunit: Clindamycin
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Antimicrobial Drugs: Mechanism of Action:Inhibition of Nucleic Acid Synthesis
• Sulfonamides & trimethoprim inhibit nucleotide synthesis,
• Quinolones inhibit DNA synthesis
• Rifampin inhibits RNA synthesis.
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Antimicrobial Drugs: Mechanism of Action: Inhibition of Protein Synthesis
Sulfonamides and trimethoprim
• Sulfonamides & trimethoprim inhibit synthesis of
tetrahydrofolic acid—main donor of methyl groups that are
required to synthesize adenine, guanine, & thymine.
• Sulfonamides are structural analogues of p-aminobenzoic
acid, which is component of folic acid.
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Antimicrobial Drugs: Mechanism of Action: Inhibition of Protein Synthesis
• Trimethoprim inhibits dihydrofolate reductase—enzyme
that reduces dihydrofolic acid to tetrahydrofolic acid.
• Combination of sulfamethoxazole & trimethoprim is used
because bacteria resistant to one drug will be inhibited by
other.
Sulfonamides and trimethoprim
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Antimicrobial Drugs: Mechanism of Action: Inhibition of Protein Synthesis
Quinolones
• Quinolones inhibit DNA synthesis in bacteria by blocking
DNA gyrase (topoisomerase)- enzyme that unwinds DNA
strands so that they can be replicated.
• Quinolones are family of drugs that includes:
- ciprofloxacin,
- ofloxacin,
-levofloxacin.
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Antimicrobial Drugs: Mechanism of Action: Inhibition of Protein Synthesis
Quinolones
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Antimicrobial Drugs: Mechanism of Action: Inhibition of Protein Synthesis
Quinolones
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• Rifampin inhibits RNA synthesis in bacteria by blocking
RNA polymerase that synthesizes mRNA.
• Rifampin is typically used in combination with other drugs
because there is high rate of mutation of RNA polymerase
gene, which results in rapid resistance to drug.
Antimicrobial Drugs: Mechanism of Action: Inhibition of Protein Synthesis
Rifampin
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Antimicrobial Drugs: Mechanism of Action: Alteration of Cell Membrane Function
• Antifungal drugs predominate in this category.
• These drugs have selective toxicity because fungal cell
membranes contain ergosterol, whereas human cell
membranes have cholesterol.
• Bacteria, with exception of mycoplasma, do not have
sterols in their membranes and therefore are resistant to
these drugs.
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Antimicrobial Drugs: Mechanism of Action: Alteration of Cell Membrane FunctionAmphotericin B
• Amphotericin B disrupts fungal cell membranes by binding
at site of ergosterol in membrane.
• It is used to treat most serious systemic fungal diseases
• It has significant side effects, especially on kidney.
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• Azoles are antifungal drugs that inhibit ergosterol
synthesis.
• The azole family includes drugs such as:
- Ketoconazole
- fluconazole
- Itraconazole
- clotrimazole.
• They are useful in treatment of systemic, skin & mucous
membrane infections.
Antimicrobial Drugs: Mechanism of Action: Alteration of Cell Membrane Function Azoles
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• Isoniazid inhibits synthesis of mycolic acid—long-chain
fatty acid found in cell wall of mycobacteria.
• Isoniazid is prodrug that requires bacterial peroxidase
(catalase) to activate isoniazid to metabolite that inhibits
mycolic acid synthesis.
• Isoniazid is most important drug used in treatment of
tuberculosis & other mycobacterial diseases.
Antimicrobial Drugs: Mechanism of Action: Additional Drug Mechanisms
Isoniazid
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• Metronidazole is effective against anaerobic bacteria &
certain protozoa
• it acts as electron sink, taking away the electrons that
organisms need to survive.
• It also forms toxic intermediates that damage DNA.
Antimicrobial Drugs: Mechanism of Action: Additional Drug Mechanisms
Metronidazole
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• Antimicrobial drugs are used to prevent infectious diseases
as well as to treat them.
• Chemoprophylactic drugs are given primarily in three
circumstances:
1. to prevent surgical wound infections
2. to prevent opportunistic infections in immuno-
compromised patients
3.to prevent infections in those known to be exposed to
pathogens that cause serious infectious diseases.
Antimicrobial Drugs: Chemoprophylaxis
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• 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.
Antimicrobial Drugs: Probiotics
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• 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 antibiotic-
associated 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.
Antimicrobial Drugs: Probiotics