Anti-Bacterial Agents I NewBB[1]

8/2/2019 Anti-Bacterial Agents I NewBB[1]

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Dr. Tara [email protected]

Tel: 01 716 6819

Anti-Bacterial Agents I

School of Biomolecular and Biomedical ScienceConway Institute
mailto:[email protected]:[email protected]


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Anti-BacterialAgents I: (i)Inhibitors of Cell Wall Synthesis

(ii) Drugs which affect Cell Membranes

Anti-BacterialAgents II: Protein Synthesis Inhibitors

Anti-BacterialAgents III: Agents which act on Nucleic Acid Synthesis

or Structure

Principles ofAntibiotic Resistance: Clinical Issues

Lecture References:

Pharmacology: Rang, Dale, Ritter and Moore, 5th or 6th Editions 2003/2007

Clinical Pharmacology: Bennett and Brown, 9th or 10th Editions 2003/2008 Extra Reading

Basic and Clinical Pharmacology: Katzung, 9th Edition 2004 Extra Extra Reading


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(i)Inhibitors of Cell Wall Synthesis

b-Lactam antibioticsObjectives of lecture:

To describe the antibiotics involved in the inhibition of cellwall synthesis, including pharmacokinetics, mechanism ofaction and side effects.


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BACTERIAL CELL WALLS

Gram + cell wall Gram - cell wall


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Summary - Cell Wall Synthesis

PLCpentapeptide

crosslinking

A

B

C

b-lactams block transpeptidase also known as penicillin binding protein (PBP)


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b-Lactam AntibioticsMechanism of Action :

Bactericidal ie : kill bacteria

Inhibit cell wall synthesis

1. Interfere with the synthesis of the bacterial cellwall peptidoglycan

2. Following attachment to the binding sites on thebacterium, they inhibit the transpeptidation

enzyme that cross-links the peptide chainsattached to the backbone of the peptidoglycan

3. Inactivation of an inhibitor of the autolyticenzymes in the cell wall leading to lysis of the

bacterium.


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Penicillins

Discovered by Alexander Fleming in 1928

Isolated from the mould - Penicllium

Bactericidal

Can be destroyed by the enzyme b-lactamase Low toxicity

Classification - 1st generation

- 2nd generation

- 3rd generation


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Structure of Penicillins

A: thiazolidine ring

B:b-lactam ring S CH3

R - C - NH - HC CH C - CH3

B A

C N CH - COOHO

b-lactamase


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Pharmacokinetics of Penicillins

Routes of Admin. : - p.o. (penicillin V / amoxycillin)

- i.v. (pipracillin)

- i.m. (penicillin G)

Absorption : reduced with food / acid pH

Protein Binding : variable

Distribution : wide all tissues and body fluids

- crosses placenta

- penetrates bone and BBB if inflamed


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Metabolism/Excretion :

mostly renalexcretion- 80 % secretion (tubular)- 20 % glomerular filtration

some renal and hepaticexcretion eg. Naficillin

- 80 % hepatic- 20 % tubular secretion by kidney

Renal excretion can be inhibited by Probenicidwhich

inhibits tubular secretion of weak acids

May need to reducethe dose of penicillin if severe renalfailure


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Side effects of Penicillins : Hypersensitivity Reactions :

A. Anaphylactic Shock circulatory collapse

oedema/spasm of bronchi

B. Serum Sickness -rash, gen.oedema, fever, adenopathy

C. Vasculitis/ interstitial nephritis / anaemia

D. Rashes /phlebitis@ injection site

GIT disturbance- nausea,vomiting, diarrhoea, colitis Neurotoxicity- seizures, myoclonis, agitation, halluc.,coma

Platelet dysfunction - immune response haemolysis

Cation toxicity - if given in salt form.

LFT / Granulocytopenia / Haemolysis

cross reactivityto cephalosporins (10%)


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Clinical uses of Penicillins

strep. sore throat, gonorrhoea, syphilis,gangrene, diptheria

boils, skin infections, cellulitis

pelvic inflammatory disease, UTI,gonococcal urethritis, H.influenzameningitis, epiglotitis

Pseudomonas (CF), Proteus infections(UTI)


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Cephalosporins

Discovered in 1945 in Sardinian sewers Isolated by Abraham + Newton (c1950s)

Isolated from fungus - cephalosporium

Bactericidal

Relatively b -lactamase resistant

Low toxicity

Classification - 1st generation (Cefalexin)

- 2nd generation (Cefachlor)

- 3rd generation (Ceftriaxone)( CSF)


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Structure of Cephalosporins

A:b-lactam ringB: Thiazolidine ring

C:b-lactamase target

S

R CO NH C C C

A B

C N C CH2 R2

O C COOH


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Side Effects of Cephalosporins

Local: thrombophlebitis, pain

Hypersensitivity reactions: similar topenicillins. (Note 10% cross

reactivitywith penicillin)

GIT: nausea, vomiting, diarrhoea

Neurotoxic: in high concentrations

Hepatotoxic: usually transient

Nephrotoxic: allergic interstitialnephritis


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Clinical Uses of Cephalosporins

Bacteremia of unknown origin.

Surgical prophylaxis.

Mixed infections especially anaerobes chest,pelvis, abdomen.

b- lactamase producing bacteria Neisseriagonorrhoea, H. influenza (3RD generation).

Gram meningitis ( 3rd generation CSF).


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Other b lactam antibiotics1. Carbapenems eg: Imipenem

Act in same way as other b-lactams Very broad spectrum cover against many

aerobic/anaerobic Gram +/- organisms includingListeria, Pseudomonas, and most Enterobacter.

Cross the inflammed BBB Many MRSA + P.aeruginosa are less susceptible

Administration is i.v.

Metabolised in the kidney by a dihydropeptidasenephrotoxic metabolite(given with cilastatin aninhibitor of this enzyme)

Similar side effect profile to other b-Lactams


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Other b lactam antibiotics

2. Monobactams eg : aztreonam Resistant to most b-lactamases

Only active against Gram aerobic rodsincluding pseudomonas, Neisseria

meningitidis and H.influenza No action against Gram+ or anaerobes

i.v. administration

Low immunogenic potential

Side effects include LFTs and

superinfection with Gram+ orgs

Renal excretion


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Other Cell Wall Synthesis InhibitorsGlycopeptide Antibiotics:

Vancomycin -inhibits release of cell wall building block

-Bactericidalexcept against Streptococci

-Effective against Gram +, also used against MRSA

-Normally give by iv but orally for GIT infections by C.difficile

-Use limited to pseudomembranous colitis, Staph infectionsin patients allergic to Penicillin and endocarditis

-Side effects include rash, fever, local phlebitis. Ototoxicityand nephrotoxicity can occur

TeicoplaninSimilar to Vancomycin but longer lasting

Other Antibiotics:

Bacitracin -inhibits dephosphorylation of lipid carrier, topical use

Cycloserinestructural analog of D-alanine, used in TB

C S


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Cell Wall SynthesisAntibacterials

PLCpentapeptide

crosslinking

A

B

C

1) b-lactams

2) Glycopeptides

3) StructuralAnalogues-Cycloserine

4) Bacitracin

Cycloserine(Structural analogue)

Vancomycin/Teicoplannin(Glycopeptide)

Bacitracin

Penicillins/Cephalosporins(b-lactams)

S


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Summary1. Major classes of antibiotics that target cell wall synthesis in

bacteria include the b-lactams2. b-lactam antibiotics consist of penicillins and cephalosporins that

contain b-lactam ring systems3. b-lactams disrupt cell wall cross-linking through inhibiting the

transpeptidase enzyme leading to cell lysis through cell wallrupture

4. Bacterial resistance to b-lactams has developed through presenceof drug degrading enzymes known as b-lactamases. Inhibitors ofthese enzymes are dispensed with penicillins in order to counteractresistance

5. New b-lactam antibiotics have been developed to deal with b-lactamase producing organisms


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(ii) Drugs which affect Cell

Membrane Function

Objectives of lecture: To discuss the antibiotics involved in affecting bacterial cellmembrane permeability including the different mechanisms ofaction, side effects and pharmacokinetics.


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Antimicrobial Therapy AffectingMembrane Function

Fluid mosaic model of membrane structure

Protein

phospholipidbilayer


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Gram+ve cell membrane

Bacterial Cell Membranes

Gram-ve cell membrane

Gram

ve outer cell membrane


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Characteristics of Bacterial Cell membrane

The plasma or cell membrane of bacterial cells issimilar to that in mammalian cells

It consists of a phospholipid bilayer in whichproteins are embedded

It can be easily disrupted in certain bacteria andfungi


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Mechanisms of Action

1. Agents that are selectively toxic to bacteriaby binding to and disrupting the structure ofthe bacterial cell membrane

2. Agents that are selectively toxic throughaffecting membrane permeability

3. Agents that are selectively toxic throughaffecting membrane enzyme systems


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Classification of Membrane-ActiveAnti-Microbial Drugs

1: Those which disorganise membrane structureTyrocidinsand gramicidin APolymixinsPolyene antibiotics (anti-fungal)

2: Those which alter membrane permeability

Gramicidins (anti-fungal)Valinomycin (anti-fungal)Enniatin (anti-fungal)Nonactin and macrotetralides (anti-fungal)Polyether antibiotics (anti-fungal)

Azoles

3: Those affecting membrane enzyme systems (all anti-fungals)OligomycinAntimycin

Some azoles

1 A h Di i M b


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1: Agents that Disorganise MembraneStructure

Tyrocidins and gramicidin A Polymixins Polyene antibiotics (not useful for bacteria)

Tyrocidins and gramicidin AMembers of the antibiotic tyrothricin discovered in

1944More active against G+ than G- bacteriaBut of little clinical application due to toxicity, usedtopically


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Polymixins Polymixins discovered 1947 (Polymixin B, Colistin)

Cationic detergent antibiotics

Peptides containing hydrophilic and lipophilic

groups

Bactericidal against Gramve bacilli(especially pseudomonads and coliforms)

Highly toxic

To reduce toxicity free amino groups replaced with

sulfomethyl groups


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Pharmacokinetics of Polymixins

Routes of admin. :- topical- parenterally (by injection)

Absorbtion: not absorbed from the gastro-intestinal tract

Side effects: May be serious side effects -

including neurotoxicity and nephrotoxicity

-Use of these drugs is limited by their toxicity-Largely confined to gut sterilisation and topicaltreatment of ear, eye or skin infections


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Mode of Action - Polymixins

Selectively bind to bacterial membranes affecting

membrane permeability and inducing loss of essentialconstituents

These compounds do not enter cell to induce effectbut diffuse into cell membrane and probably displaceMg2+and Ca2+

Fatty acid group facilitates diffusion into membrane

Binding involves membrane phospholipids so morepotent toward G- as these contain more phospholipid,

especially pseudomonads and coliform organisms


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Summary1. Membrane active agents can be classified as to

whether they affect membrane structure, permeabilityor membrane associated enzyme systems

2. Agents that affect membrane structure includepolyenes, tyrocidins and polymixins

3. Membrane permeability is affected by ionophores suchas valinomycin and nonactin. These compoundscomplex small cations primarily K+ and facilitate their

transport through the membrane

4. Membrane permeability is also affected by the azoleswhich can bind to bacterial fatty acids. Azoles can alsoinhibit bacterial nucleic acid formation

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Anti-Bacterial Agents I NewBB[1]

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