Antibiotics affecting the cell envelope

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Dr. Alvin Fox
Antibiotics affecting the cell envelope
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Key Words
Sterilization/disinfection/antisepsis Vancomycin
Antibiotic beta lactam
Selective toxicity Penicillins
Bactericidal Cephalosporins/cephamycins
Bacteriostatic Monobactam
Minimal inhibitory concentration (MIC) Clavulinic acid
Susceptibility testing Polymyxin B
Penicillin binding proteins Isoniazid
Penicillinase/beta lactamase Ethioniamide
Autolysins Ethambutol
Cycloserine Resistance
Bacitracin
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STERILIZATION
All killed
non-selective
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Sterilization

autoclaving
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


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Membrane filters
pores
bacteria
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Disinfection
Liquids that kill bacteria
e.g. phenol based
too toxic for skin surfaces
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Antiseptics
Topical (e.g. skin)
e.g. iodine or 70% alcohol
“reduce” bacterial load

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ANTIBIOTICS
Selectively toxic for bacteria
bactericidal (killing)
bacteriostatic (growth inhibition)

minimize harm to patient
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Antibiotics
destroy structures
present in bacteria
not present in host
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Antibiotics work together
with 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

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Cross-linking of peptidoglycan
Old
New
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Peptidoglycan synthesis
Cytoplasm
Cell wall
undecaprenol
sugar
amino
acid
Cell Membrane
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Cycloserine
X
Cytoplasm
sugar
amino
acid
X
X
X
alanine (ala) analog
- inhibits conversion L-ala to D-ala
- inhibits formation of D-ala-D-ala
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Bacitracin
Inhibits dephosphorylation
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TRANSPORT OF PEPTIGOGLYCAN SUBUNIT ACROSS MEMBRANE
Cell membrane
undecaprenol
P

P
Cell wall
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TRANSPORT OF PEPTIGOGLYCAN SUBUNIT ACROSS MEMBRANE
Cell membrane
undecaprenol
P

Cell wall
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TRANSPORT OF PEPTIGOGLYCAN SUBUNIT ACROSS MEMBRANE
Cell membrane
undecaprenol
P
P
Cell wall
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TRANSPORT OF PEPTIGOGLYCAN SUBUNIT ACROSS MEMBRANE
Cell membrane
undecaprenol
P
P
Cell wall
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TRANSPORT OF PEPTIGOGLYCAN SUBUNIT ACROSS MEMBRANE
Cell membrane
undecaprenol
P

P
Cell wall
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MINUS BACITRACIN
Cell membrane
undecaprenol
P

Cell wall
TRANSPORT OF
PEPTIGOGLYCAN SUBUNIT
ACROSS MEMBRANE
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PLUS Bacitracin
Cell membrane
undecaprenol
P
P
Cell wall
TRANSPORT OF
PEPTIGOGLYCAN SUBUNIT
ACROSS MEMBRANE
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Vancomycin
Cell wall
binds to D-ala-D-ala
inhibits cross-linking
Vancomycin
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Beta lactam antibiotics
penicillins
Cephalosporins/cephamycins
monobactams
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β lactams
Cell wall
Penicillin binding protein
inhibit penicillin binding proteins

stop cross-linking
β lactam
Active site
of enzyme
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Site of penicillinase action.
Breakage of the β lactam ring.
STRUCTURE OF PENICILLIN
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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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β lactam
binds strongly to β lactamases
inhibits activity
limited potency as antibiotic
used in conjunction with other β lactams



Clavulinic acid
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Polymyxin B

binds
lipid A
phospholipids
disrupts outer membrane, Gram negative bacteria
toxic to human cells
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Isoniazid, Ethambutol, Ethionamide  
Isoniazid and Ethionamide
- chemically related
- blocks mycolic acid synthesis
Ethambutol
- blocks arabinogalactan synthesis
Anti-tuberculosis drugs