09 lecture 19 (pharm beta-lac vanco i)mid 19 beta-lactamases - cleave the beta-lactam ring -...
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MID 19
Beta-lactam antibiotics
Penicillins
Target - Cell wall - interfere with cross linkingActively growing cells
Bind to Penicillin Binding Proteinsg
Enzymes involved in cell wall synthesis
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MID 19
Activity of an Antibiotic
Affinity for target
Permeability properties (ability to get to the target)
Stability to bacterial enzymatic degradationy y g
Bacterial modifications:
1 – Mutate target - ? More than one protein Importance of the targetImportance of the target –? Essential
2. Permeability – Size/charge considerations? Substrate for an efflux pump
3. Selection for mutants that destroy the antibiotic3. Selection for mutants that destroy the antibiotic
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MID 19
WHO discovered the penicillins??
Abess Hildegarde von Bingen ?
“Good things that grow on the sides of trees….”
Fleming –Fleming –
Florey – WWII….
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MID 19
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MID 19
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MID 19
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MID 19
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MID 19
Penicillin binding proteins
Transpeptidasesp p
Carboxypeptidases
Differ in Gram (+) and in Gram (-) bacteria
Differ in abundance
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MID 19
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MID 19
Activity of the beta-lactam antibiotic:
ff f ’ ( f f )Affinity for critical PBP’s (number of copies of the target)
Ability to get to the target (permeability properties –more of an issue for Gram negs)
Stability to beta-lactamases - degradationStability to beta-lactamases - degradation
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MID 19
Beta-lactamases - cleave the beta-lactam ring -inactivate the drug -Open ring - can’t bind to the target
Co-evolved with the penicillin binding proteins
Share a ser-X-X-lys - binding site for interactions
G iti S t d i t th i tGram positives - Secreted into the environmentGram negatives - Secreted into the periplasmic space
ANTI-staphylococcal penicillins
“semi-synthetic”
Add bulky side chains to provide
STERIC HINDRANCE to protect the Beta-lactam nucleus –
Gram positives – secrete bla’s – “cloud”
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MID 19
Anti-staphylococcal penicillins
Strategy - Add a bulky side group to block beta-lactamase
(Methicillin) - renal toxicityNafcillinOxacillinCloxacillin (di-clox) - oral drugsCloxacillin (di-clox) - oral drugs
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MID 19
Beta-lactamase secretion in Gram positive andGram negative bacteria
Periplasmic Space – Gram Negative
Capsule – No barrier
Peptidoglycan –No barrierNo barrier
Outer wall – PorinsControl access
Cytoplasmic Membrane – LipidMembrane LipidBilayer
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MID 19
Beta-lactamases
Regulation - Consititutive - Chromosomal (E.coli)
Plasmid mediated -copy number dependent
Inducible - chromosomal - SPACE organisms - as a model
2-component signaling - (ampD, ampE, ampR)SensorResponse regulatorTranscriptional activator
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MID 19
Drugs in clinical use:
Penicillin G, VK
Ampicillin (+) clavulanic acid (beta lactamase inhibitor)Ampicillin (+) clavulanic acid (beta-lactamase inhibitor)
(oral or parenteral)
Piperacillin - anti-Pseudomonas (+tazobactam)(parenteral)
Spectrum - gram positive and gram negative -Not inherently beta-lactamase stableSpectrum - dependent upon permeability properties
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MID 19
Add a beta-lactamase inhibitor
Clavulanic acidClavulanic acid -SulbactamTazobactam
Expands spectrum of activityAnaerobes
NOT effective against the beta-lactamases of the SPACE organisms
Tazobactam
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MID 19
30e
3rd generation cephalosporin-resistant Kliebsiella pneumoniae Among ICU
Patients,1995-2004
5
10
15
20
25
Perc
ent R
esis
tanc
e
0
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
Year
P
Source: National Nosocomial Infections Surveillance (NNIS) System
Pharmacology of the penicillins
Absorption - Amoxicillin - acid stabledosing - give more - longer intervalsAugmentin - amox + clav - diarrheaAugmentin amox + clav diarrhea
Metabolism - minor
Excretion - Renal - tubular secretionIncrease serum levels with probenecid
Biliary - only ureido penicillinsy y pNafcillin
Distribution - Anions - charged - extracellular spaceCSF - with inflammationConcentrated in urine