In the antibiotic war, a new weapon is needed

By Michael Vinegrad

Earlier this year, antibiotic resistance was selected as the focus for the £10m Longitude Prize, set up to tackle major challenges of our time.

The World Health Organization has warned of a ‘post-antibiotic era’ where key drugs no longer work and people die from previously treatable infections, and Prime Minister David Cameron has warned the world will be ‘cast back into the dark ages of medicine’ unless action is taken. Drug resistant tuberculosis, gonorrhea and Klebsiella are already occurring around the world and MRSA is a growing issue. The problem is exacerbated by overuse (link is external) and the fact that there has not been a new class of antibiotics discovered (link is external) since the 1980s.
But how do antibiotics actually work, and why are we losing the war with bacteria?
Antibiotics wage a molecule on molecule war inside bacteria. The antibiotic drug molecule binds to a target within the bacteria, which could be proteins, nucleic acids or membrane constituents of the bacteria. In doing so they interfere with the life processes of the microorganism. The bacteria then cannot sustain its existence due to the interaction of drug and target. It eventually dies because it can’t cope with the problems the drug has caused. Sounds great, doesn’t it?
But antibiotics are a specific weapon that disrupt particular molecular processes. For example, penicillin binds to enzymes that are involved in the assembly of cell walls. The cell wall maintains the bacterial cell structure and helps to prevent infection, so it is critical for bacteria to survive. Penicillin inhibits cell wall biosynthesis, or ‘bursts’ the cell walls open, killing the bacteria. Although penicillin was the first antibiotic discovered, all beta-lactam antibiotic drugs share the same cell wall busting mechanism.
This predictable line of attack has made it easier for bacteria to fight back and evolve. Just as antibiotics disrupt critical molecules in the bacteria’s lifecycle, bacteria in turn find ways to neutralise antibiotics – by producing enzymes such as beta-lactamase, or even by reshaping their molecules. And given it only takes bacteria 30 minutes to reproduce it is easy to see why we are losing the war. The trouble is bacteria have been around for a few billion years longer than us. So they are, in evolutionary terms at least, older and wiser.
Fresh ideas are clearly needed, and some promising work is underway – such as the work currently going on at the Scripps Research Institute. They have successfully synthesized a new antibiotic (link is external) that exhibits impressive potencies against resistant bacteria. And the new drug has two independent mechanisms of action, meaning that bacteria are unlikely to rapidly acquire resistance.
It is not yet clear where the next generation of antibiotics will come from. But it appears that a new, innovative approach is badly needed to outsmart the wise old bacteria. The clock is ticking and the Longitude Prize is there for the taking.