Among the most powerful weapons in our antibiotic arsenal are aminoglycosides, which can prevent the biosynthesis of key proteins that infectious bacteria such as Staphylococcus aureus and Escherichia coli need to survive. First isolated in the 1950s, several aminoglycoside antibiotics like neomycin were developed over the ensuing decades. More recently, however, some strains of bacteria have developed resistance to these agents by producing enzymes that can alter the function of amino and hydroxyl groups within the molecule so that it can no longer penetrate bacterial cells.

Neomycin, currently used as a topical ointment for minor skin infections, is being rescued from possible obsolescence by researchers at Université de Montréal. The team, which includes chemistry professor Stephen Hanessian, initially examined the possibility of simply removing a hydroxyl group from neomycin to limit the effectiveness of the aminoglycoside-inactivating enzyme. Although activity was improved, this modification also introduced the prospect of potential side effects. Instead, they synthesized an analogue of neomycin, with an axial fluorine atom in place of one of its OH groups, a modification that has been shown to resist the action of some inactivating enzymes. “Fluorine is a very important element in medicinal chemistry,” says Hanessian. “It replaces hydrogen because of its small size but it also brings with it electronic effects since fluorine is an electronegative element — it just pulls electrons from its surroundings.”

Hanessian adds that this change also decreases the basicity of aminoglycosides, another desirable result, since it will limit the potential toxicity to humans. So far the result has only been demonstrated in vitro, but it should be possible to insert fluorine into the molecular structure of other drugs in order to assess changes in how they interact with their targets. This has been a common practice in drug design. 

In collaboration with Jiro Kondo of Sophia University in Tokyo, the UdeM research group included postdoctoral associates Miguel Vilchis and Oscar Saavedra, as well as graduate student Juan Pablo Maianti. Antibacterial testing was done courtesy of Achaogen Inc. of South San Francisco, Calif. X-ray crystallography revealed the binding properties of the modified aminoglycosides with bacterial ribosomes and the results were recently published in Chemical Science as an “Edge Article.”  

Meanwhile, as satisfying as it has been to manipulate the structure of this molecule to create a specific effect, Hanessian is looking forward to learning more about the underlying mechanisms of this change. “What we see is only a three-dimensional picture but not in real time, although what we have is good enough to design new analogues,” he says.