anti-bacterial agents i newbb[1]
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Dr. Tara McMorrowtara.mcmorrow@ucd.ie
Tel: 01 716 6819
Anti-Bacterial Agents I
School of Biomolecular and Biomedical ScienceConway Institute
mailto:tara.mcmorrow@ucd.iemailto:tara.mcmorrow@ucd.ie -
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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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