Polymyxins are relatively simple, highly basic peptides
with molecular weights of about 1000 daltons.
- They are amphipathic, surface-active
- agents (containing both lipophilic and hydrophilic groups within the molecule) that act as ‘cationic detergents’.
In other words, they have a hydrophobic head
(which serves as the FUEL of the molecule
because it has Carbons
molecules) and the hydrophilic tail
, which is very polar
and water soluble
because of the many amino groups on it. Therefore, this hydrophobic tail
allows the molecule to be positively charged
in a physiologic pH, and therefore the molecule can act like soap
, a cationic detergent
They are capable of penetrating the outer membrane (cell wall)
bacteria through porin channels
to act on the inner cell membrane (The much thicker cell wall of Gram-positive
bacteria is an effective barrier to penetration by the polymyxins). So Polymixins are active against Gram Negative
and NOT Gram Positive
They bind ionically to phospholipids
(recall that on the phospholipid bilayer you have negatively charged phosphate groups on the outside that will attract the positively charged Polymixin molecule
) and penetrate into the structure of cell membranes
. As a result, they disrupt cell membrane permeability
They also bind to phospholipids of the outer membrane
bacteria, which contributes to the overall sensitivity of these organisms to the polymyxins
In vivo activity of the polymyxins is decreased by the presence of divalent cations
- The cell wall of certain resistant Gram-negative species (Proteus and Serratia) may prevent access of the polymyxins to the cell membrane.
- Cell membrane permeability changes immediately on contact with the polymyxins, resulting in the loss of intracellular components that are essential to the survival of the cell.
such as calcium, which is believed to interfere with the binding of the drug to the cell membrane