Molecules that drill holes in bacteria and make them spring a fatal leak could become the next weapon in the war against antibiotic-resistant superbugs.
Unlike most antibiotics, these 鈥渉ydraphile鈥� molecules are not based on the bug-killing compounds found naturally in organisms such as fungi. Instead, they mimic the tiny 鈥渋on channels鈥� embedded in the membranes of living cells. But while ion channels control the movement of particular ions into and out of cells, hydraphiles let them flow freely in and out. This wrecks the delicate balance needed to keep the cell alive (see Graphic).
Hydraphiles work by forming a tunnel right through the membrane. At each end of the molecule is a ring-like structure called a 鈥渃rown ether鈥�, which is negatively charged. This pulls positive ions such as calcium and sodium into the tunnel. Each hydraphile has another crown ether 鈥渞elay鈥� halfway along its length to maintain the ions鈥� momentum through the tunnel.
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Experiments reported this month in the Journal of the American Chemical Society (vol 124, p 9022) demonstrate for the first time that hydraphiles can indeed insert themselves into cell membranes, and the team has used them to kill a strain of the bacterium E. coli that is resistant to the antibiotic ampicillin.
鈥淲e assume that when hydraphiles insert, ions flow in both directions,鈥� says George Gokel, head of the team that created hydraphiles at Washington University School of Medicine in St Louis, Missouri. He says that seems to be enough to disrupt the ion concentration gradients that the cell maintains across its membrane, thereby killing it.
The team鈥檚 latest work has shown that hydraphiles only work if they are long enough to span the target cell鈥檚 membrane. Gokel hopes to turn this to his advantage by making hydraphiles that can kill bacterial cells but are too short to harm human cells. It might also be possible to modify hydraphiles so that they only embed in the cell membranes of certain bacteria and fungi, he says.