Agents Attacking the Cell Membrane

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Agents Attacking the Cell Membrane
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Cell Membrane
Precursor biosynthesis
Respiration
15 classes including Antimycin Blastomycin Nitroi
midazole Nitrofurantoin
Triclosan Isoniazid Ethionamide Cerulenin Thiolact
omycin Naftidin Azoles
Structural integrity
Pore/channel forming Amphotericin
B Nystatin Gramicidin A Alamethicin Suzukacillin
Monazomycin Rofalomycin
Halophenols Chlorhexidines Polymixins Tyrocidin Gr
amicidin S Filipin Flavofungion Etruscomycin Defen
sins
Ionophores
13 classes including Monensin Nigericin Laslocid S
alinomycin
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Precursor biosynthesis
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Triclosan
Originally assumed to be a non-specific
antiseptic and has been widely used in household
products.
Now known to be a specific inhibitor of
enoyl-ACP reductase and that resistance can occur
through point mutation.
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Isoniazid
Selective agent for Mycobacteria. Important
part of tuberculosis chemotherapy. Recently
found to be activated by catalase to make a
specific inhibitor of enoyl-ACP reductase.
Resistance can occur through point mutations
that inactivate catalase or that decrease
affinity for target.
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Structural Integrity
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Chlorhexidine
In absence of chlorhexidine
In presence of chlorhexidine
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Gramicidin S
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Polymixin B
Cationic lipopeptide, binds to negatively charged
groups on the Gram-negative cell wall and
disrupts membrane. Resistance achieved by
enzymes that add amino-arabinose to cell wall,
increasing positive charge.
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Colistin

• A member of the polymixin family
• Use discontinued during 1980s because of
  associated
• nephrotoxicity
• Now being re-evaluated as a last resort for
  treatment of
• infections caused by multi-resistant
  Gram-negative bacteria

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Pore/channel forming Peptides
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Gramicidin A
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Insect Anti-microbial Peptides
Cecropins are small amphiphilic peptides produced
by insects in response to stresses such as
bacterial infection. They work, like gramicidins
and polymixins, to collapse ion-gradients and
trigger lysis.
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Amphibian dermal secretions
Magainins are small amphiphilic peptides produced
by frogs and toads. They collapse ion-gradients
and cause lethal swelling of many bacteria.
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Defensins antimicrobial peptides of human origin
Defensins are small, soluble polypeptides
secreted by the Paneth cells located in the
invaginations of the intestinal epithelium. They
cause lysis of many bacteria
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Amphotericin B Nystatin
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Amphotericins
Macrocyclic lactones that bind to cholesterol
containing membranes to form pores. Important
anti-fungal agents
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Mobile Ionophores
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Valinomycin
Forms complex with K (Cs). Valine residues form
a hydrophobic shell arund the ion.
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Valinomycin
The free antibiotic and the lipid-soluble cation
complex diffuse freely across the membrane,
allowing the K concentration to reach
equilibrium across the membrane
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Nigericin
The free antibiotic and the lipid-soluble cation
complex diffuse freely across the membrane,
allowing the H/K concentration to reach
equilibrium across the membrane
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Monensin and Salinomycin
Salinomycin
Very similar in structure to nigericin, but form
a slightly smaller clathrate shell. Thus, more
selective for Na