Antibiotic binding: X-rays show us the sites

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  • Published: Dec 1, 2017
  • Author: David Bradley
  • Channels: X-ray Spectrometry
thumbnail image: Antibiotic binding: X-rays show us the sites


Fragment-based screening identifies novel targets for inhibitors of conjugative transfer of antimicrobial resistance by plasmid pKM101 Credit: Baron et al/Sci Rep)

Researchers at the Université de Montréal, Canada, are using X-ray crystallography to find the exact binding site for small molecules that can attach and thus inhibit the bacterial protein, TraE (transfer operon E), which is an essential component of the plasmid transfer machinery of bacterial resistance.

Emerging bacterial resistance to antibiotic drugs is a growing concern across the globe with the World Health Organization and other international bodies emphasising that part of the problem is their use in non-bacterial infection. Given that antibiotics are essential part of preventative medicine in surgery and in cancer therapy. We urgently need to find replacements for the failing drugs and to better understand how to design novel antibiotics that are less prone to the mechanisms of bacterial resistance.

One way in which bacteria share the genes that give them antibiotic resistance whether in hospitals or the wider public environment is through plasmid transfer between bacteria. A plasmid is a fragment of DNA that carries genes useful for bacteria. Of particular concern is that plasmids can carry genes that encode proteins to circumvent the mode of action of a given antibiotic. Now a team at the Université de Montréal's Department of Biochemistry and Molecular Medicine has devised a new approach to blocking the transfer of such resistance genes. Details of the research by Bastien Casu, Tarun Arya, Benoit Bessette and Christian Baron are reported in the journal Scientific Reports.

Small molecule library

The team screened a library of small molecules that bind to TraE protein and used X-ray analysis to examine the precise binding site. Such information then helped guide the researchers in their design of analogues of the most potent small molecules in their library so that they could inhibit the process of plasmid transfer and thus block of antibiotic resistance. Baron hopes that the strategy might be used to discover new inhibitors of the transfer of resistant genes.

"You want to be able to find the 'soft spot' on a protein, and target it and poke it so that the protein cannot function," explains Baron. "Other plasmids have similar proteins, some have different proteins, but I think the value of our study on TraE is that by knowing the molecular structure of these proteins we can devise methods to inhibit their function."

Resisting resistance

Baron and his colleagues are now sharing their data with medicinal chemist colleagues in IRIC (Institut de recherche en immunologie et cancérologie) to develop new drugs that are will be potent inhibitors of plasmid transfer. Such molecules might eventually be added to the arsenal of pharmaceuticals used in hospitals where resistance to conventional drugs is rife. Ultimately, reducing the transfer of antibiotic-resistance plasmids could help preserve the potency of current antibiotics and might thus contribute to an overall strategy to help improve human health.

"The beauty of what we are working on here is that the proteins are very similar to proteins that bacteria use to cause disease. So from what we learned about the TraE protein and about finding its 'soft spot,' we can actually apply this approach to other bacteria that cause diseases. One of those is Helicobacter pylori, which is a gastric pathogen that causes ulcers and stomach cancers. We're working on that one specifically now, but there are many others."

Related Links

Sci Rep 2017, online: "Fragment-based screening identifies novel targets for inhibitors of conjugative transfer of antimicrobial resistance by plasmid pKM101"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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