Fighting superbugs with supercomputers

We’re losing the arms race against superbugs. Now with the aid of a supercomputer, Alan Grossfield at the University of Rochester is refining a new battlefield strategy. Instead of attacking their proteins, which bacteria can disguise, the new weapons attack the membrane which is much harder to hide. Grossfield and his team’s findings were published in Biophysical Journal in August.

In this arms race “the cell membrane is like the final frontier”, says University of Queensland microbiologist Matt Cooper.

Last year, the UK Review on Antimicrobial Resistance estimated that antibiotic resistant bacteria account for at least 700,000 deaths each year and could grow to 10 million worldwide by 2050. If we want to avoid entering a post-antibiotic era we need new armaments.

Most antibiotics are designed to latch on to and deactivate a single protein target in the cell. Penicillin, for example, blocks an enzyme bacteria need to hold their cell wall together. However, bacteria can rapidly mutate these protein targets making them unrecognisable to the antibiotics.

But bacteria are far less able to mutate the structure of their membranes; their basic life chemistry relies on it. So drugs that attack the bacterial membrane should be harder to beat.

Tree frogs discovered this trick long ago. Their skin contains a host of antimicrobial and antifungal defences – including a group called lipopeptides that slice bacterial membranes, making them leaky. Medicinal chemists are now developing lipopeptides of their own, to be used as antimicrobial drugs. The first, daptomycin, is the only new antibiotic to be approved by the US Food and Drug Administration in the past 15 years.

Researchers hope to make other lipopeptide drugs that are even more potent that daptomycin. The problem is that human cells also have membranes – so when designing membrane-slicing drugs, it’s important that bacteria remain their sole target. Grossfield looked more closely at one lipopeptide drug in development, already shown to clear bacterial infections in mice, in order to understand how the drug worked.

Antimicrobial lipopeptides clump together in roughly spherical clusters known as micelles. They float through the bloodstream with their weapons hidden – like a Swiss army knife with all its blades folded away. Only when a clump reaches a target do the blades flip out to pierce the membrane.

With the help of a supercomputer, Grossfield’s team simulated how the drug responded when stuck to a bacterial and mammalian membrane. This drug’s action takes less than 500^th of a second, but the simulations took an entire year of number crunching.

It turns out the drug has a slight positive charge. Luckily mammalian membranes are neutral, so the drug doesn’t stick. But bacterial membranes are negatively charged. Once stuck, the drug’s “blades” quickly flick out and slice into the membrane. The team found the drug stabbed bacterial membranes 50 orders of magnitude faster than mammalian membranes. “This was really cool,” Grossfield says.

In this computer simulation, the lipopeptide cluster (green and yellow) sticks to the bacterium’s surface (blue), and then all of a sudden (12 seconds through the video) slices its way into the bacterium’s membrane.
Credit: Dejun Lin, University of Rochester Medical Centre

He also found there’s a sweet spot to the drug’s blade length. If they’re too long, they tend to get jammed in the clump. Too short, and they don’t inflict enough damage to kill the bacterium.

He hopes his work will help chemists design better lipopeptides in the future: “I hope I can explain to the medicinal chemists what drug properties they should think about.”

The new drugs will buy us more time, but even this strategy is not likely to last. Some bacteria have already found a defence against daptomycin, first membrane-stabbing drug, which was rolled out in 2003.

Cooper believes over-prescription of antibiotics is the biggest contributor to resistance. But “attacking the membrane gives us more time”, he says. “We want to find drugs that give us a couple of decades.”