Antibiotics affecting the cell envelope

Dr. Alvin Fox

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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 2
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 Membrane Cell wall

undecaprenol

sugar

amino
acid

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 Cycloserine
alanine (ala) analog
Cytoplasm - inhibits conversion L-ala to D-ala
- inhibits formation of D-ala-D-ala

X X
sugar

amino
acid

X 15
X
 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 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

MINUS BACITRACIN 22
 TRANSPORT OF
PEPTIGOGLYCAN SUBUNIT
ACROSS MEMBRANE
Cell membrane Cell wall

undecaprenol

P
P

PLUS Bacitracin 23
 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
Cell wall
•inhibit penicillin
β lactam
binding proteins

•stop cross-linking
Active site
of enzyme

Penicillin binding protein

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STRUCTURE OF PENICILLIN

O
S
CH3
C NH CH CH C
CH3
O C N CH 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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Isoniazid, Ethambutol, Ethionamide  
Anti-tuberculosis drugs
Isoniazid and Ethionamide
- chemically related
- blocks mycolic acid synthesis
Ethambutol
- blocks arabinogalactan synthesis

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