Download Antibiotics cell envelope

Antibiotics: cell envelope,
Lecture 28
Dr. Alvin Fox
1
Key Words
Sterilization/disinfection/antisepsis
Beta lactam
Antibiotic
Penicillins
Selective toxicity
Cephalosporins/cephamycins
Bactericidal
Monobactam
Bacteriostatic
Clavulinic acid
Minimal inhibitory concentration (MIC) Penicillinase/beta lactamase
Susceptibility testing
Polymyxin B
Penicillin binding proteins
Daptomycin
Autolysins
Isoniazid
Cycloserine
Ethioniamide
Bacitracin
Ethambutol
Vancomycin
Resistance
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STERILIZATION
• All killed
• non-selective
3
• autoclaving
Sterilization
– 121oC (heat/pressure)
* Heat resistant materials
• ethylene oxide
– non heat resistant
– Usually equipment
– being replaced e.g. H2O2/free radicals
• ultra-violet light
– surfaces (e.g. operating rooms)
not totally effective
• gamma radiation
– mainly food industry
4
Membrane filters
pores
bacteria
5
Disinfection
• Liquids that kill bacteria
– e.g. phenol based
– too toxic for skin surfaces
6
Antiseptics
• Topical (e.g. skin)
– e.g. iodine or 70% alcohol
– “reduce” bacterial load
7
ANTIBIOTICS
• Selectively toxic for bacteria
– bactericidal (killing)
– bacteriostatic (growth inhibition)
• minimize harm to patient
8
Antibiotics
• damage structures
– present in bacteria
– not present in host
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Antibiotics work together
with the immune system
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Minimal inhibitory
concentration
• lowest level stopping growth
• e. g. zone of inhibition around a disk
impregnated with antibiotic
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• Antibiotics that inhibit cell wall
biosynthesis are bactericidal
• Without cell wall, osmotic pressure
causes bacteria to burst
12
Cross-linking of peptidoglycan
Old
New
13
Peptidoglycan synthesis
Cytoplasm
Cell Membrane
Cell wall
undecaprenol
sugar
amino
acid
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Cycloserine
Cytoplasm
alanine (ala) analog
- inhibits conversion L-ala to D-ala
- inhibits formation of D-ala-D-ala
X X
sugar
amino
acid
X
X
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Bacitracin
• Inhibits dephosphorylation
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TRANSPORT OF
PEPTIGOGLYCAN SUBUNIT
ACROSS MEMBRANE
Cell membrane
Cell wall
undecaprenol
P
P
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TRANSPORT OF
PEPTIGOGLYCAN SUBUNIT
ACROSS MEMBRANE
Cell membrane
Cell wall
undecaprenol
P
P
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TRANSPORT OF
PEPTIGOGLYCAN SUBUNIT
ACROSS MEMBRANE
Cell membrane
Cell wall
undecaprenol
P
P
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TRANSPORT OF
PEPTIGOGLYCAN SUBUNIT
ACROSS MEMBRANE
Cell wall
Cell membrane
undecaprenol
P
P
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TRANSPORT OF
PEPTIGOGLYCAN SUBUNIT
ACROSS MEMBRANE
Cell membrane
Cell wall
undecaprenol
P
P
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TRANSPORT OF
PEPTIGOGLYCAN SUBUNIT
ACROSS MEMBRANE
Cell membrane
Cell wall
undecaprenol
P
MINUS BACITRACIN
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TRANSPORT OF
PEPTIGOGLYCAN SUBUNIT
ACROSS MEMBRANE
Cell membrane
Cell wall
undecaprenol
P
P
PLUS Bacitracin
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Vancomycin
Cell wall
Vancomycin
• binds to D-ala-D-ala
• inhibits cross-linking
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Beta lactam antibiotics
• penicillins
• cephalosporins/cephamycins
• monobactams
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β lactams
•inhibit penicillin
binding proteins
Cell wall
β lactam
•stop cross-linking
Active site
of enzyme
Penicillin binding protein
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STRUCTURE OF PENICILLIN
O
S
C
NH
CH
O
C
CH
N
CH3
C
CH
CH3
COOH
Site of penicillinase action.
Breakage of the β lactam ring.
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Attached to lactam ring
• penicillins
– 5 membered ring
• Cephalosporins/cephamycins
– 6 membered ring
• monobactams
– no second ring
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Chemical modifications change
biological activity
• Early lactam antibiotics
– inactive against Gram negative
bacteria
• no penetration of outer membrane
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Resistance mechansims
• Produce β lactamase (penicillinase)
– destroys antibiotic
• modified penicillin binding proteins
– don’t bind antibiotic
• modified porins
– no internalization of antibiotic
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Clavulinic acid
• β lactam
• binds strongly to β lactamases
– inhibits activity
• limited potency as antibiotic
• used in conjunction with other β lactams
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Polymyxin B
• binds
– lipid A
– phospholipids
• disrupts outer membrane, Gram negative bacteria
• toxic to human cells
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Daptomycin
• Causes depolarization of bacterial cell
membrane
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Anti-tuberculosis drugs
Isoniazid and Ethionamide
- chemically related
- blocks mycolic acid synthesis
Ethambutol
-blocks arabinogalactan synthesis
Cycloserine
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