Scientists observe in detail the binding and formation of covalent bonds of an inhibitor to a bacterial enzyme that disables common antibiotics
Antibiotic resistance is a major and particularly in recent years growing challenge in medicine. Scientists around the world are searching for new and efficient compounds to treat bacterial infections, especially infections caused by multi-resistant bacteria. A research collaboration of scientists from DESY, University Medical Center Eppendorf (UKE) in Hamburg and Universität Hamburg performed time-resolved diffraction experiments at PETRA III to observe at near atomic resolution and at the millisecond timescale the inhibition of a bacterial enzyme that nullifies a common class of antibiotics, the β-lactams. The results have been published in Nature Communications Chemistry.
Among antibiotics, beta-lactams are the classics. Penicillin, the first commercially produced antibiotic and the related derivatives from penicillin belong to this class of pharmaceuticals. At the beginning of the 21st century, half of the antibiotics used worldwide applied were beta-lactams. However, even since the beginning of the use of penicillin, bacteria have evolved defences against antibiotics. One of the defences is an enzyme called beta-lactamase. Like a molecular pair of scissors, beta-lactamase cuts the central ring of the beta-lactam molecule and disables its antibiotic properties – allowing the bacteria to keep living.
Worldwide and for the last 20 years scientists have been searching for a way to disable beta-lactamase in an effort to directly combat antibiotic resistance. Until now, most of the candidate beta-lactamase inhibitors that have been examined have been organic compounds that mimic penicillin, allowing the inhibitor to enter the enzyme’s active site and block it. However, today’s bacteria can potentially resist these molecules after around one or two years as well. A different avenue of research has taken to using far more basic molecules to block the active site of the enzyme.
“There are new boric acid-based beta-lactamase inhibitors, and they are really potent,” says Andreas Prester, the first author of the PETRA III study and a postdoc at UKE. “For example, boron-containing compounds and drugs were developed to be used for the treatment for multiple myeloma, a form of blood cancer.” In terms of pilot investigations and a drug re-purposing approach, the research collaboration identified the potential of boron-based compounds to inhibit beta-lactamases as well. “Since then we’ve studied these inhibitors in more detail, as well as their potential to inhibit beta-lactamses,” Prester adds.
Prester and his colleagues, Markus Perbandt from Universität Hamburg, Winfried Hinrichts, an emeritus professor from the University of Greifswald, and Christian Betzel, a professor at Universität Hamburg who led the research have been among those examining the inhibition caused by boric acid in detail. Using the European XFEL and PETRA III, they examined how the boric acid binds to the enzyme. At PETRA III, the team around DESY lead scientist Henry Chapman helped assemble an experiment at the beamline P11 using a mechanism that could show at atomic resolution, like a movie, the progress of boric acid binding, in this case, to the amino acid serine within the active site. “It’s a relatively stable bond, and the boric acid then blocks the ability of the enzyme to interact with the antibiotic,” says Prester.
Read more on DESY website
Image: Using PETRA III’s X-ray beam, the scientists were able to watch how boric acid inhibits the beta-lactamase enzyme.
Credit: Universitätsklinikum Hamburg-Eppendorf UKE, Andreas Prester