Designing better antibiotics

How High-Throughput Compute helped 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. Fungi cause all kinds of damage, from pneumonia in the lungs to 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. Unfortunately, AmB is very toxic to the human body and may create even more problems. The challenge is to develop an improved version of AmB with the efficiency of the original and fewer side effects.

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.

AmB has a slight preference to attach to the membranes of fungal cells. But the affinity is not strong and it explains why the antibiotic also attacks human cells: it sometimes can’t tell the difference between them.

Neumann analysed the problem with molecular dynamics simulations and used the computing resources provided by the Polish National Grid Initiative for her research. For that she needed 24 computing cores for each grid job submitted, adding up to a total of five million CPU hours. The results show that the 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 will allow Neumann 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,” Neumann concludes.

Three-dimensional model of the Amphotericin B molecule. (Source: wiki commons)

References

A. Neumann, M. Baginski and J. Czub. 2010. How Do Sterols Determine the Antifungal Activity of Amphotericin B? Free Energy of Binding between the Drug and Its Membrane Targets. Journal of the American Chemistry Society, 132: 18266–18272. doi:10.1021/ja1074344 (abstract)