Tag: antibiotic

V-161: A Breakthrough in the Fight against Antibiotic-Resistant VRE Infections

V-161: A Breakthrough in the Fight against Antibiotic-Resistant VRE Infections

V-161 targets a crucial enzyme in VRE, offering promise in combating antibiotic-resistant infections in hospital environments

V-161, a novel compound targeting the Na+-V-ATPase enzyme in vancomycin-resistant Enterococcus faecium (VRE), significantly reduces bacterial growth and colonization. A recent study has demonstrated a promising approach for fighting antibiotic resistance by identifying a compound, V-161, that inhibits a sodium-pumping enzyme critical for VRE survival under alkaline conditions in the intestine while preserving beneficial bacteria. This breakthrough offers hope for treating hospital infections and tackling the global threat of antibiotic-resistant bacteria.

The rise of antibiotic-resistant bacteria is a global health concern, with studies projecting over ten million deaths annually by 2050 due to these resistant infections. The World Health Organization (WHO) has identified twelve critical antibiotic-resistant pathogens, including vancomycin-resistant Enterococci (VRE), such as Enterococcus faecium (E. faecium). VRE causes severe hospital-acquired infections like endocarditis and sepsis and has developed resistance to multiple antibiotics, highlighting the urgent need for new antimicrobial treatments.

In response to this crisis, a team of researchers led by Professor Takeshi Murata from the Graduate School of Science, Chiba University, Japan, has discovered a promising new compound, V-161, which effectively inhibits the growth of VRE. Their research examined a sodium-pumping enzyme found in these bacteria called Na+-transporting V-ATPase found in E. hirae, a close relative of E. faecium, used as a safer, more tractable model for studying the enzyme. The team consisted of Assistant Professor Kano Suzuki, first author from the Graduate School of Science, Chiba University; Associate Professor Yoshiyuki Goto from the Medical Mycology Research Center, Chiba University; Professor Toshiya Senda and Associate Professor Toshio Moriya from the Structural Biology Research Center, High Energy Accelerator Research Organization; and Professor Ryota Iino from the Institute for Molecular Science, National Institutes of Natural Sciences. This study, published online in Nature Structural & Molecular Biology on November 21, 2024, hypothesized that Na+-transporting V-ATPase could play a key role in the development of an antibiotic that specifically targets VRE without affecting beneficial bacteria.

Read more on Photon Factory website

New compounds to combat antibiotic resistance

New compounds to combat antibiotic resistance

To address the global threat of antibiotic resistance, scientists are on the hunt for new ways to sneak past a bacterial cell’s defence system. Taking what they learned from a previous study on cancer, researchers from the University of Toronto (U of T) have developed novel compounds that trigger bacterial cells to self-destruct.

The new form of antibiotics is designed to target a naturally occurring enzyme — caseinolytic protease proteolytic subunit, ClpP, for short — which chews up old or defective proteins and plays an essential role in cellular housekeeping. The new compound kicks the ClpP enzyme into overdrive, so it begins chewing up proteins that it is not supposed to, eventually killing its own cell from the inside out. Video: New compounds to combat antibiotic resistance

“Most antibiotics inhibit a process,” says Dr. Walid A. Houry, professor of biochemistry at the University of Toronto. “With this approach, we are dysregulating a process, and this allows us to develop this new class of compounds that we eventually hope to get into a clinic.” Houry worked closely with Dr. Robert Batey and colleagues to build upon their previous work in this area.

“It turns out that the [enzyme] present in cancer cells is also present in bacteria. For this project, the tricky thing was trying to find a way to hit the bacterial ClpP, but not the human ClpP.” Houry said.

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Using PETRA III to watch the disabling of a penicillin killer

Using PETRA III to watch the disabling of a penicillin killer

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