MECHANISMS OF ACTION OF ANTIBIOTICS. BACTERIOSTATIC AGENTS Sulfonamides Drugs inhibiting protein...

MECHANISMS OF ACTION OF ANTIBIOTICS

BACTERIOSTATIC AGENTS

Sulfonamides

Drugs inhibiting protein synthesis except aminoglycosides (macrolides, chloramphenicol, tetracyclines etc).

BACTERICIDAL AGENTS Beta lactams (penicillins, cephalosporins,

imipenem)

Trimethoprim/sulfamethoxazole

Vancomycin

Fluoroquinolones

Aminoglycosides

MECHANISMS OF ACTION Inhibitors of cell wall synthesis

Drugs altering cell membranes

Inhibitors of protein synthesis

Antimetabolites

Inhibitors of nucleic acid synthesis.

DRUGS INHIBITING CELL WALL SYNTHESIS Penicillins

Cephalosporins

Imipenem

Vancomycin

Fosfomycin

β-lactams

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Plus penicillin

Spheroplast

Emerging Spheroplast

Dividing Bacteria

Division

Growth site

Growth

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Mur NAc

X

Glycopeptide Polymer

X

Mur NAc

Glycopeptide Polymer

X

Glycopeptide Polymer

D-Alanine

Transpeptidase

Penicillin Binding Proteins

Transpeptidases

Carboxypeptidases

Endopeptidases

Penicillin

AUTOLYSINS

All Beta lactam antibiotics act by the same mechanism

PENICILLINS ACTIVE VS GRAM - BACTERIA

S

C

CC

C

C

N COOHO

CH3

CH3NCO

R

Penicillinase

S

C

CC

C N COOH

CH3

CH3NCO

R

OHO

Penicilloic Acid

(β-Lactamase)

COMBINATIONS WITH BETA LACTAMASE INHIBITORS

Penicillin plus a beta lactamase inhibitor.

CEPHALOSPORINS AND IMIPENEM

Same mechanism of action as penicillins but bind to different binding proteins.

FOSFOMYCIN

Inhibits peptidoglycan synthesis at an earlier stage than where the beta lactams act.

VANCOMYCIN

Enzyme

Enzyme

NAG-NAM

D-ALA

L-GLU

LYS

D-ALA

D-ALA

Transpeptidase

PENICILLINS

X

NAG-NAM

D-ALA

L-GLU

LYS

D-ALA

D-ALA

Enzyme

VAN

Transglycosylase

RESISTANCE TO BETA LACTAMS

Penicillinase Beta lactamases

S

C

CC

C

C

N COOHO

CH3

CH3NCO

R

Penicillinase

S

C

CC

C N COOH

CH3

CH3NCO

R

OHO

Penicilloic Acid

METHICILLIN RESISTANCE

Altered PBP’s.

RESISTANCE TO OTHER BETA LACTAM ANTIBIOTICS

Most prevalent mechanism is hydrolysis by beta lactamases.

Cephalosporins have variable susceptibility to βlactamases.

Some even induce formation of the enzymes.

RESISTANCE TO VANCOMYCIN

ANTIBIOTICS AFFECTING CELL MEMBRANES

Polymyxins Daptomycin

POLYMYXINS

Surface active amphipathic agents.

Interact strongly with phospholipids and disrupt the structure of cell membranes.

DAPTOMYCIN

Depolarizes the cell membrane

ANTIBIOTICS INHIBITING PROTEIN SYNTHESIS

Macrolides Clindamycin Linezolid Streptogramins Chloramphenicol Tetracyclines Aminoglycosides

50S

30S

Procaryotic Ribosome

70S--M.W.2,500,000

60S

40S

Eucaryotic Ribosome

80S--M.W. 4,200,000

Antibiotics binding to the 50S ribosomal subunit and inhibiting protein synthesis

Erythromycin and other macrolides

Chloramphenicol

Linezolid

Streptogramins

Antibiotics binding to the 30S ribosomal subunit and inhibiting protein synthesis

Aminoglycosides

Tetracyclines

CLEanS AT

Macrolides (Erythromycin, Azithromycin and Clarithromycin)

aa

A50S

30S

mRNA

template

Transferase site

P

Nascent polypeptide chain

MACROLIDES

TRANSLOCATION

CHLORAMPHENICOL

aa

A50S

30S

mRNA

template

Transferase site

P

Nascent polypeptide chain

Chloramphenicol

Mechanism of action of Chloramphenicol

INITIATION

STREPTOGRAMINS

Quinupristin/Dalfopristin (30:70)

aa

A50S

30S

mRNA

template

Transferase site

P

Nascent polypeptide chain

QUINUPRISTIN(MACROLIDE)

DALFOPRISTIN

INITIATION

AMINOGLYCOSIDES

Bind irreversibly to the 30S subunit.

Exact mechanism of cell death is unknown.

Postantibiotic effect.

A50S

30S

mRNA

template

Transferase site

P

Nascent polypeptide chain

Tetracycline

aa

INHIBITION OF MITOCHONDRIAL PROTEIN SYNTHESIS

Mitochondrial ribosome resembles bacterial ribosome.

May account for some toxic effects (e.g. chloramphenicol, linezolid).

RESISTANCE

Alterations in ribosomal proteins (e.g. macrolides).

Decreased permeability to the antibiotic.

TetracyclineATP

TETRACYCLINE RESISTANCE

ANTIBIOTICS ACTING AS ANTIMETABOLITES

Sulfonamides

Trimethoprim plus sulfamethoxazole

2HN COOH

DIHYDROPTERIDINE

PYROPHOSPHATE DERIVATIVE

DIHYDROPTEROIC ACID

DIHYDROFOLIC ACID

FOLIC ACID BIOSYNTHESIS

Glutamic Acid

2 ATP

2HN SO2NH2

Dihydropteroate

Synthetase

TRIMETHOPRIM-SULFAMETHOXAZOLE

2HN CH2

OCH3

OCH3

OCH3

80 mg TRIMETHOPRIM

O

2HN SO2NH

N CH3

400 mg SULFAMETHOXAZOLE

PABA

DIHYDROPTEROIC ACID

DIHYROFOLIC ACID

TETRAHYDROFOLIC ACID

+ Pteridine

SULFONAMIDE

TRIMETHOPRIMDihydrofolate Reductase

Dihydrofolate Synthetase

Dihydropteroate Synthetase

Advantages of sulfonamide-trimethoprim combination

Results from multiple mechanisms.

Altered dihydropteroate synthetase.

Cross-resistance among all sulfonamides.

SULFONAMIDE-RESISTANCE

ANTIBIOTICS AFFECTING NUCLEIC ACID SYNTHESIS.

Fluoroquinolones

Metronidazole

Rifampin

FLUOROQUINOLONES

FLUOROQUINOLONES

Gyrase (Topoisomerase I)-older quinolones

Topoisomerase IV-3rd and 4th gen quinolones.

FQ RESISTANCE

Changes in gyrase and topoisomerase

Increased efflux

Inactive End ProductsInactive End Products

MetronidazoleMetronidazole

MetronidazoleMetronidazole

Short lived Short lived intermediatesintermediates

Inactive endInactive end productsproducts

DNADNARNARNA

ProteinProteinOther targetsOther targets

Mechanism of Mechanism of action of action of metronidazole on metronidazole on an anaerobic an anaerobic organismorganism

Ferredoxin Ferredoxin reducedreduced

RIFAMPIN