Designing better antibiotics
How grid computing is helping to develop antibiotics with less side effects but equally powerful against fungi.
Diseases caused by fungi are a real risk for people burdened with weak immune systems, for example after organ transplants or long chemotherapy treatments. The fungi can do all kinds of damage, from causing pneumonia in the lungs to attacking the brain with vicious types of meningitis, or triggering life-threatening infections.
The antibiotic Amphotericin B – abbreviated as AmB – has been the drug of choice to fight fungal infections for the past 50 years. It’s brutally efficient, killing a broad spectrum of fungal agents and active against all known multidrug resistant strains.
The catch is that AmB is toxic to the human body and it can cause organ damage in patients, especially in the kidneys.
The challenge is to develop an upgraded version of AmB, with all the efficiency of the original but fewer side effects.
Human vs fungal cells: what’s the difference
Anna Neumann has been working on this problem for her PhD at the University of Technology in Gdansk, Poland. “We know how AmB works on a cellular level – that it acts on a cell membrane, and forms some kind of permeable structures, most probably channels, in it,” she explains. The channels built by the AmB allows the cell contents to leak out eventually leading to cell death.
The problem is that AmB is not very discerning and attacks the human cells together with the infectious fungi cells it’s supposed to kill. This is because there is not much difference between the way this antibiotic interacts with fungal and human cell membranes.
The keys to solving this problem are the compounds known as sterols – the gatekeepers of cell membranes. Sterols control the physical and chemical properties of the membrane, for example how permeable they are. The sterol in fungal cells is called ergosterol; mammals have a different type, called cholesterol.
AmB has a slight preference to attach itself to membranes containing ergosterol (and hence kill the fungal cells), but this affinity is not strong and it explains why the antibiotic also attacks human cells: it sometimes can’t tell the difference between them.
So, learning more about how AmB connects to the two types of cells and their sterols, how the antibiotic enters the cell membrane and how the channels are formed, will help create safer AmB varieties. Anna analysed the problem with molecular dynamics simulations – computer models designed to mimic the physical movements of atoms and molecules.
Using the grid to make better antibiotics
Molecular dynamics models are very useful for describing the behaviour of atoms and molecules and their interactions, but are also very demanding in terms of computing power. For her research, Anna accessed the computing resources provided by the Polish National Grid Initiative to process the molecular dynamic simulations. She used 24 computing cores for each grid job that was submitted, adding up to a total of five million CPU hours.
According to the results published in the Journal of the American Chemical Society, the difference in AmB’s affinity for ergosterols and cholesterols is partially due to energy levels. It’s easier, in terms of energy, for AmB to interact with the rigid and elongated molecular geometry of the ergosterol than with the cholesterol. In other words, AmB needs more energy to combine with human cells than with fungal cells and it is usually the lower energy option that wins out.
These conclusions, together with further analysis, will allow Anna to propose a way to make the AmB molecule more likely to attach itself to fungal cells. “That would affect AmB's activity – making it more selective for fungal cells and hence less toxic,” Anna concludes.