1.4.5 Inhibitors of cell membrane function

The cell membrane controls the passage of substances into and out of the cell. Inhibitors of the cell membrane function interfere with the cell membrane’s structure, causing cell contents to leak out, and eventually leading to cell death.

Daptomycin is a cell membrane inhibitor that is used to target Gram-positive bacteria. You may recall that Gram-positive cells have a large peptidoglycan cell wall, covering the plasma membrane. Daptomycin binds with calcium ions to form a calcium complex. The addition of the calcium to form the calcium complex means that the daptomycin can insert itself into the plasma membrane. The complexes then aggregate within the plasma membrane to form pore-like structures that allow ions to leak out of the cell, eventually leading to cell death (Figure 14). Daptomycin is a relatively new antibiotic and is not in widespread use, which may explain why resistance, for now, is rare.

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Figure 14 Daptomycin (red) forms a complex with calcium which inserts into the cell membrane (blue) creating a pore like structure which allows ions (black) to leak out of the cell.

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This figure shows the mechanism of action of daptomycin. A section of the cell membrane is represented as a bilayer. The daptomycin molecule is shown on the outside of the membrane as a red circle with a long tail. In step 1, calcium binding and insertion, a daptomycin molecule is shown bound to calcium. The tail of this molecule is inserted into the membrane so that the tail sits within the membrane bilayer. The ‘head’ of the molecule sits on the outside surface of the membrane. In step 2, oligomerisation and channel formation, three calcium bound daptomycin molecules are shown inserted into the membrane (as in step 1) and clustered together. In step 3, ion efflux, a cluster of four calcium-bound daptomycin molecules is depicted as a channel, or pore, in the membrane. These molecules have their tails inserted into the membrane and the ‘head’ of the molecules sit on the outside surface of the membrane. There are potassium ions on either side of the channel made by the daptomycin molecules, on the inside and outside of the membrane. An arrow running through the channel indicates the direction of movement of the potassium ions from the inside of the membrane to the outside.

Figure 14 Daptomycin (red) forms a complex with calcium which inserts into the cell membrane (blue) creating a pore like structure which ...

Polymyxins, such as colistin, are another group of cell membrane inhibitors that are used to target Gram-negative cells. Remember, the Gram-negative cell has an additional outer membrane that is not present in Gram-positive cells. Polymyxins bind to the lipopolysaccharides within the outer membrane, causing structural changes to the membrane. This in turn causes a loss of membrane integrity, increasing its permeability. The polymyxins are now able to pass through the proteoglycan wall and reach the plasma membrane, disrupting it in a similar way. This causes the cell contents to leak out, eventually leading to cell death.