Batterjee Medical College. Dr. Manal El Said Department Head of Microbiology Antimicrobial Drugs:...

Batterjee Medical College


Dr. Manal El SaidDr. Manal El Said Department Head of Microbiology

Antimicrobial Drugs: Mechanism of Action


• 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






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



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



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).


• 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.



• 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-Bacteria can grow again when drug is withdrawn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.





• 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.



Inhibition of Cell Wall

Synthesis


• 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



Penicillins



Penicillins

Gram-negative Gram-positive


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 Cross-Linking of Bacterial Cell Wall Subunits

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.

Penicillins



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.

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.

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 .

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 gram-positive bacteria decreases.

Penicillins



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).

Penicillins



Penicillins


methicillin

nafcillin

oxacillin


• 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



Cephalosporins



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



Carbapenems



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.



• 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.


Vancomycin



Vancomycin


• Caspofungin is lipopeptide that inhibits fungal cell wall

synthesis by blocking synthesis of β-glucan,

polysaccharide component of cell wall.


Caspofungin


Inhibition of Protein

Synthesis


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


• 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


30S ribosomal subunit :Aminoglycosides



30S ribosomal subunit :Aminoglycosides


• 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.


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.


• Chloramphenicol inhibits bacterial protein synthesis by

blocking peptidyl transferase, enzyme that adds new amino

acid to growing polypeptide.

• Chloramphenicol can cause bone marrow suppression.


50S ribosomal subunit: Chloramphenicol


• 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.


50S ribosomal subunit: Erythromycin


• 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.


50S ribosomal subunit: Clindamycin


Inhibition of Nucleic

Acid Synthesis


Antimicrobial Drugs: Mechanism of Action:Inhibition of Nucleic Acid Synthesis

• Sulfonamides & trimethoprim inhibit nucleotide synthesis,

• Quinolones inhibit DNA synthesis

• Rifampin inhibits RNA 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.



• 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



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.



Quinolones



Quinolones


• 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.


Rifampin


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.


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.


• 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


• 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


• 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


• 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


• 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


• 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.






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Batterjee Medical College. Dr. Manal El Said Department Head of Microbiology Antimicrobial Drugs:...

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