It all happens in a femtosecond 鈥� a quadrillionth of a second. That鈥檚 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鈥檛 trigger bacterial resistance.
In 1946, Nobel laureate Linus Pauling suggested that enzymes are most active during fleeting transition states, but only recently has at the Albert Einstein College of Medicine in Yeshiva University, New York, moved the science from the blackboard to the clinic. 鈥淭he problem in this whole field has been no one really knew what the structure of an enzyme鈥檚 transition state looked like,鈥� he says. 鈥淚t鈥檚 hard to see something that has [effectively] no lifetime.鈥�
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鈥� reactive forms 鈥� like a baseball clamped to a catcher鈥檚 mitt 鈥� that the enzyme is essentially taken out of action.
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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鈥檚 drugs are at a more advanced stage. Two are in clinical trials 鈥� one to treat gout and the other for leukaemia.
Lower dosage
of the University at Buffalo, New York, who formerly worked in Schramm鈥檚 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. 鈥淵ou can鈥檛 get that from other drug development approaches unless you鈥檙e just plain fortuitous,鈥� he says.
Schramm鈥檚 work may even hold the key to developing antibiotics that don鈥檛 trigger resistance in bacteria. Traditional antibiotics lay waste to most bacteria, but some cells inevitably survive, and their mutated genes 鈥� which are the source of resistance 鈥� 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 鈥� and the cholera-causing pathogen Vibrio cholerae 鈥� 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.
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