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
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 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.
Batterjee Medical College
Antimicrobial Drugs: Mechanism of
Action: Introduction
• 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.
Batterjee Medical College
Antimicrobial Drugs: Mechanism of
Action: Introduction
Batterjee Medical College
Antimicrobial Drugs: Mechanism of
Action: Introduction
• 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.
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Inhibition of Cell Wall
Synthesis
Batterjee Medical College
Antimicrobial Drugs: Mechanism of
Action: Inhibition of Cell Wall Synthesis
Penicillins
• Penicillins
&
transpeptidases
cephalosporins
act
(penicillin-binding
by
inhibiting
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.
Batterjee Medical College
Antimicrobial Drugs: Mechanism of
Action: Inhibition of Cell Wall Synthesis
Penicillins
Batterjee Medical College
Antimicrobial Drugs: Mechanism of
Action: Inhibition of Cell Wall Synthesis
Penicillins
Gram-negative
Gram-positive
Batterjee Medical College
Antimicrobial Drugs: Mechanism of
Action: Inhibition of Cell Wall Synthesis
Penicillins
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
Role of Penicillin Binding Protein in CrossLinking of Bacterial Cell Wall Subunits
Batterjee Medical College
Antimicrobial Drugs: Mechanism of
Action: Inhibition of Cell Wall Synthesis
Penicillins
• 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.
Batterjee Medical College
Antimicrobial Drugs: Mechanism of
Action: Inhibition of Cell Wall Synthesis
Penicillins
Batterjee Medical College
Antimicrobial Drugs: Mechanism of
Action: Inhibition of Cell Wall Synthesis
Penicillins
• 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.
Batterjee Medical College
Antimicrobial Drugs: Mechanism of
Action: Inhibition of Cell Wall Synthesis
Penicillins
• 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.
Batterjee Medical College
Antimicrobial Drugs: Mechanism of
Action: Inhibition of Cell Wall Synthesis
Penicillins
• 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 .
Batterjee Medical College
Antimicrobial Drugs: Mechanism of
Action: Inhibition of Cell Wall Synthesis
Penicillins
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 grampositive bacteria decreases.
Batterjee Medical College
Antimicrobial Drugs: Mechanism of
Action: Inhibition of Cell Wall Synthesis
Penicillins
Batterjee Medical College
Antimicrobial Drugs: Mechanism of
Action: Inhibition of Cell Wall Synthesis
Penicillins
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).
Batterjee Medical College
Antimicrobial Drugs: Mechanism of
Action: Inhibition of Cell Wall Synthesis
Penicillins
oxacillin
methicillin
nafcillin
Batterjee Medical College
Antimicrobial Drugs: Mechanism of
Action: Inhibition of Cell Wall Synthesis
Cephalosporins
• Cephalosporins have six-membered ring adjacent to βlactam ring &
are substituted in two places on 7-
aminocephalosporanic acid nucleus (penicillins have fivemembered ring & are substituted in only one place).
• First-generation cephalosporins are active against grampositive cocci
• Second, third, & fourth generations have expanded
coverage against gram-negative rods.
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Antimicrobial Drugs: Mechanism of
Action: Inhibition of Cell Wall Synthesis
Cephalosporins
Batterjee Medical College
Antimicrobial Drugs: Mechanism of
Action: Inhibition of Cell Wall Synthesis
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
Batterjee Medical College
Antimicrobial Drugs: Mechanism of
Action: Inhibition of Cell Wall Synthesis
Carbapenems
Batterjee Medical College
Antimicrobial Drugs: Mechanism of
Action: Inhibition of Cell Wall Synthesis
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.
Batterjee Medical College
Antimicrobial Drugs: Mechanism of
Action: Inhibition of Cell Wall Synthesis
Vancomycin
• 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.
Batterjee Medical College
Antimicrobial Drugs: Mechanism of
Action: Inhibition of Cell Wall Synthesis
Vancomycin
Batterjee Medical College
Antimicrobial Drugs: Mechanism of
Action: Inhibition of Cell Wall Synthesis
Caspofungin
• Caspofungin is lipopeptide that inhibits fungal cell wall
synthesis
by
blocking
synthesis
polysaccharide component of cell wall.
of
β-glucan,
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Inhibition of Protein
Synthesis
Batterjee Medical College
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
Batterjee Medical College
Antimicrobial Drugs: Mechanism of
Action: Inhibition of Protein Synthesis
30S ribosomal subunit :Aminoglycosides
• 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
Batterjee Medical College
Antimicrobial Drugs: Mechanism of
Action: Inhibition of Protein Synthesis
30S ribosomal subunit :Aminoglycosides
Batterjee Medical College
Antimicrobial Drugs: Mechanism of
Action: Inhibition of Protein Synthesis
30S ribosomal subunit :Tetracyclines
• 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.
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.
Batterjee Medical College
Antimicrobial Drugs: Mechanism of
Action: Inhibition of Protein Synthesis
50S ribosomal subunit: Chloramphenicol
• Chloramphenicol inhibits bacterial protein synthesis by
blocking peptidyl transferase, enzyme that adds new amino
acid to growing polypeptide.
• Chloramphenicol can cause bone marrow suppression.
Batterjee Medical College
Antimicrobial Drugs: Mechanism of
Action: Inhibition of Protein Synthesis
50S ribosomal subunit: Erythromycin
• 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.
Batterjee Medical College
Antimicrobial Drugs: Mechanism of
Action: Inhibition of Protein Synthesis
50S ribosomal subunit: Clindamycin
• 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.
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Inhibition of Nucleic
Acid Synthesis
Batterjee Medical College
Antimicrobial Drugs: Mechanism of
Action:Inhibition of Nucleic Acid Synthesis
• Sulfonamides & trimethoprim inhibit nucleotide synthesis,
• Quinolones inhibit DNA synthesis
• Rifampin inhibits RNA synthesis.
Batterjee Medical College
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.
Batterjee Medical College
Antimicrobial Drugs: Mechanism of
Action: Inhibition of Protein Synthesis
Sulfonamides and trimethoprim
• 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.
Batterjee Medical College
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.
Batterjee Medical College
Antimicrobial Drugs: Mechanism of
Action: Inhibition of Protein Synthesis
Quinolones
Batterjee Medical College
Antimicrobial Drugs: Mechanism of
Action: Inhibition of Protein Synthesis
Quinolones
Batterjee Medical College
Antimicrobial Drugs: Mechanism of
Action: Inhibition of Protein Synthesis
Rifampin
• 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.
Batterjee Medical College
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.
Batterjee Medical College
Antimicrobial Drugs: Mechanism of
Action: Alteration of Cell Membrane Function
Amphotericin 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.
Batterjee Medical College
Antimicrobial Drugs: Mechanism of
Action: Alteration of Cell Membrane Function
Azoles
• 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.
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Antimicrobial Drugs: Mechanism
Action: Additional Drug Mechanisms
of
Isoniazid
• 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.
Batterjee Medical College
Antimicrobial Drugs: Mechanism
Action: Additional Drug Mechanisms
of
Metronidazole
• 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.
Batterjee Medical College
Antimicrobial Drugs:
Chemoprophylaxis
• 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.
Batterjee Medical College
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.
Batterjee Medical College
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