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MECHANISMS OF ACTION OF ANTIBIOTICS

Mechanisms of ActionKnow the mechanism of action to the depth in summary sheets.

Know the reason for selective toxicity for each group of antibiotics.

Know whether each antibiotic is bactericidal or static.

Know resistance mechanism for beta lactams.

BACTERIOSTATIC AGENTS

Sulfonamides

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

BACTERICIDAL AGENTSBeta lactams (penicillins, cephalosporins, imipenem)

Trimethoprim/sulfamethoxazole

Vancomycin

Fluoroquinolones

Aminoglycosides

MECHANISMS OF ACTIONInhibitors 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

www.chem.qmul.ac.uk/

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Mur NAc

X

Glycopeptide Polymer

X

Mur NAc

Glycopeptide Polymer

X

Glycopeptide Polymer

D-Alanine

Transpeptidase

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Penicillin Binding Proteins

Transpeptidases

Carboxypeptidases

Endopeptidases

PENICILLIN

AUTOLYSINSCEPHALOSPORINS AND IMIPENEM

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

PENICILLINS ACTIVE VS GRAM - BACTERIA

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S

C

CC

C

C

N COOHO

CH3CH3NC

OR

Penicillinase

S

C

CC

C N COOH

CH3CH3NC

OR

OHO

Penicilloic Acid

(β-Lactamase)

COMBINATIONS WITH BETA LACTAMASE INHIBITORS

Penicillin plus a beta lactamase inhibitor.

FOSFOMYCIN

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

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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

PenicillinaseBeta lactamases

RESISTANCE

Increased production of beta-lactamase (penicillinase) enzymes.

S

C

CC

C

C

N COOHO

CH3CH3NC

OR

Penicillinase

S

C

CC

C N COOH

CH3CH3NC

OR

OHO

Penicilloic Acid

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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

PolymyxinsDaptomycin

POLYMYXINS

Surface active amphipathic agents.

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

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DAPTOMYCIN

It binds to bacterial membranes resulting in depolarization of the, loss of membrane potential and cell death.

ANTIBIOTICS INHIBITING PROTEIN SYNTHESIS

MacrolidesClindamycinLinezolidStreptograminsChloramphenicolTetracyclinesAminoglycosides

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

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

Aminoglycosides

TetracyclinesCLEanS 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

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INITIATION

STREPTOGRAMINS

Quinupristin/Dalfopristin (30:70)

aa

50S

30S

mRNA

template

Transferase site

P

Nascent polypeptide chain

QUINUPRISTIN(MACROLIDE)

ADALFOPRISTIN

MECHANISM OF ACTION

Act synergistically to inhibit bacterial protein synthesis.

They bind to separate sites on the 50 S ribosomal subunit and form a ternary complex with the ribosome.

MECHANISM OF ACTION

Quinupristin binds at the same site as the macrolides and has a similar effect.

Dalfopristin directly blocks peptide bond formation by inhibiting peptidyl transferase.

Dalfopristin results in a conformational change in the 50S ribosome subunit.

INITIATION

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AMINOGLYCOSIDES

Bind irreversibly to the 30S subunit.

Exact mechanism of cell death is unknown.

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.

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TetracyclineATP

INCREASED EFFLUX OUT OF THE CELL 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

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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

FLUOROQUINOLONES

FLUOROQUINOLONES

DNA Gyrase (Topoisomerase II)-older quinolones

Topoisomerase IV-3rd and 4th

generation quinolones.

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Inactive End Products

Metronidazole

Metronidazole

Short lived intermediates

Inactive endproducts

DNARNAProtein

Other targets

Mechanism of action of metronidazole on an anaerobic organism

Ferredoxinreduced