Penicillin acts like a mousetrap. Credit to Dreamstime
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Penicillin is stacked high in pharmacies and hospitals across the globe and proven in combat against bronchitis, pneumonia and pharyngitis. However, this ‘wonder drug’ that once reigned supreme on the front line of World War Two is under attack. With antibiotic resistance rising from the trenches in the battle against bacteria, the demand for new ‘wonder drugs’ is sparking scientific interest.
We report the first successful characterisation of a natural antibiotic using neutrons, 85 years after its chance discovery by Alexander Fleming.
Using a rational approach to scientific experiments where trial and error take a back seat, a collaboration of scientists from Queen Mary University of London, ISIS, The University of Toronto, The University of Szeged and Beijing Normal University have used neutrons to uncover the complexity at the core of this natural wonder in the hope it will facilitate the rational understanding and design of new antibiotics. They used the TOSCA instrument at ISIS to study how penicillin acts as a system – likening it to a mousetrap – luring with bait, sensing prey and then springing into action to trap and kill the prey. Their research has been published as a highlight article in the RSC journal Physical Chemistry Chemical Physics.
“We call it molecular gesturing or co-operative motions” explains Dr Gregory A. Chass (School of Biological and Chemical Sciences, QMUL) “A very small part of penicillin initiates a cascade or domino effect; the mouse trap model is really an artistic impression of the systemic properties. If you remove any of the components or if you were to swap them round then you would lose the function.”
“It’s a complex system; however we can use neutrons to tackle complexity. Grasping an understanding of how penicillin works opens up the possibility to recreate the systemic properties.”
Penicillin manages to escape the clutches of metabolic degradation sailing successfully through bodily fluids. It uses a process called acylation to inactivate the enzymes that generate bacterial cell walls. You can equate the bacterial wall to the foundations of a building – omission leads to collapse. Without such support the bacteria rupture. Penicillin owes its ability to remain inactive in transit to its systemic properties; the molecular smokescreen allowing it to engage its target.
Dr Greg Chass explains “it’s inactive when it sits on the shelf, it’s inactive in the capsule, it’s inactive in your stomach and bloodstream - it’s only when it gets to the target bacteria that penicillin becomes active. It goes from completely inactive to specifically active. We want to know, how it knows how to do that?’’
Neutrons reveal the catalytic mechanics behind penicillin’s precision.
Dr Greg Chass and his team adopted an approach combining theory with experiment. “The approach to scientific experiments is changing; we can now draw-up a theoretical blueprint and then test our theory by putting it into simulation, from which we design cost-effective experiments.” This is what Dr Chass calls “knocking up a plan on a (slightly used) napkin while at the cafe”. Using a combination of inelastic neutron spectroscopy, NMR and Quantum chemical theory the team have revealed that penicillin operates as a system similar to modern catalysts.
Catalysts, likewise have targeted activities and specificities, with the vast majority of products in use today manufactured by direct or indirectly catalysed processes. Nature’s catalysts – including enzymes – are considered to be the most efficient and offer tangible solutions to standing industrial and environmental problems, if their efficacy can be understood and harnessed.
Building on the successes emerging from the penicillin project, new and exciting neutron and muon beam experiments are ongoing. Experiments are being designed for other bioactive molecules – including those found in green tea, coffee, olive oil, red wine, traditional Chinese medicines and even hand-made doughs and noodles. Systems that Dr. Chass refers to as “The most important ones to research. Ones that most people can comfortably relate to and definitely want to know more about!”. Industries which command historic and huge market presence – and fall under the ‘healthy ageing’ grand challenge areas of the UK’s research councils, and those in the EU/EEA.
Gregory Chass et al.
Research date: February 2013
Mucsi Z, Chass GA, Abrányi-Balogh P et al. (2013) . Penicillin's catalytic mechanism revealed by inelastic neutrons and quantum chemical theory.Phys Chem Chem Phys
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