It all happens in a femtosecond – a quadrillionth of a second. That’s the time an enzyme needs to shape-shift into its most reactive form, trigger a chemical reaction and snap back into its original shape. We can now enter this high-speed world to interrupt the chemical reactions that sustain some of our deadliest pathogens and cause disease. Doing so could lead to antibiotics that won’t trigger bacterial resistance.

In 1946, Nobel laureate Linus Pauling suggested that enzymes are most active during fleeting transition states, but only recently has Vern Schramm at the Albert Einstein College of Medicine in Yeshiva University, New York, moved the science from the blackboard to the clinic. “The problem in this whole field has been no one really knew what the structure of an enzyme’s transition state looked like,” he says. “It’s hard to see something that has [effectively] no lifetime.”

Over the course of a decade, Schramm has reconstructed those states, using computational and molecular modelling techniques. He has used the results to build drugs that bind so tenaciously to different enzymes’ reactive forms – like a baseball clamped to a catcher’s mitt – that the enzyme is essentially taken out of action.

One of his drugs neutralises a key enzyme in the malaria parasite, Plasmodium falciparum. Owl monkeys infected with usually lethal malaria cleared the illness after a week-long course of the drug.


Some of Schramm’s drugs are at a more advanced stage. Two are in clinical trials – one to treat gout and the other for leukaemia.

Lower dosage

Andrew Murkin of the University at Buffalo, New York, who formerly worked in Schramm’s lab, is in the early stages of developing a similar drug, designed to tackle tuberculosis. He says that these drugs are so well tailored to block a specific enzyme that there is the potential to lower the dosage needed for efficacy. “You can’t get that from other drug development approaches unless you’re just plain fortuitous,” he says.

Schramm’s work may even hold the key to developing antibiotics that don’t trigger resistance in bacteria. Traditional antibiotics lay waste to most bacteria, but some cells inevitably survive, and their mutated genes – which are the source of resistance – spread through the population.

To prevent this, we need antibiotics that cure the disease without killing the bacteria, so the bugs are not put under evolutionary pressure to mutate. Schramm has identified a promising target: an enzyme used in bacterial communication. We already know that bacteria which cannot communicate are far less virulent, but no less successful at eking out a living, than their communicating brethren.

Schramm has developed a drug that blocks an enzyme that Escherichia coli – and the cholera-causing pathogen Vibrio cholerae – use to communicate. Lab results are impressive: the drug is as effective against the 26th generation as it is against the first. The next step is to find a company to develop the drug further.

Journal reference: PLoS One, DOI: 10.1371/journal.pone.0026916