Native state mass spectrometry could identify drugs to fight resistant bacteria
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A technique called native state mass spectrometry could allow scientists to evaluate how potential inhibitors work on antibiotic-resistant bacteria, according to a study presented at the World Microbe Forum.
“The primary focus of our lab’s research is determining the mechanism of inhibition of potential metallo-beta-lactamase (MBL) inhibitors using a variety of spectroscopic techniques,” Caitlyn A. Thomas, MS, a PhD candidate in chemistry at Miami University, told Healio. “In addition, our lab has extensively studied the evolution of the most clinically relevant metallo-beta-lactamases,” including New Delhi metallo-beta-lactamase 1 (NDM-1), Verona integron-encoded metallo-beta-lactamase 2 (VIM-2) and IMP-1.
Metallo-beta-lactamases can make many clinically relevant strains of bacteria resistant to all penicillin-like antibiotics.
Thomas explained that imipenemase (IMP) was found to evolve to overcome the structural differences of beta-lactam antibiotics and the IMP-1 variant, IMP-78, has two mutations close to the active site and it showed the most drastic change in resistance to some beta-lactams compared with IMP-1.
“Previously, I have studied the mechanism of inhibition of a variety of inhibitors with VIM-2 optimizing the use of native state mass spectrometry, so, this combination led me to ask the question of whether variants would be inhibited in the same way as their parent,” Thomas said. “For example, if an inhibitor worked with IMP-1 — if it was capable of binding to and inhibiting IMP-1 — would it also be capable of inhibiting IMP-78?”
Thomas and colleagues used molecular modeling and native state mass spectrometry quick screening a unique technique that keeps the protein in the native state instead of fragmenting the sample, as would occur with other mass spectrometry techniques to determine if a variety of inhibitors would be capable of inhibiting IMP-1 and the variant IMP-78.
Thomas said the study is ongoing. but so far, it has shown that there are differences of inhibition between IMP-1 and IMP-78.
“I have found some of the inhibitors I am studying are capable of binding to IMP-1, but they do not bind to IMP-78,” she said. “That means they are exhibiting different mechanisms of inhibition with the parent and variant enzymes.”
According to Thomas, the study has both immediate and long-term implications. Immediately, it highlighted the fact that variants of IMP-1 are unique and potentially exhibit different mechanisms of inhibition when compared with IMP-1. In the long-term, this means that scientists will need to account for these differences in designing future inhibitors.
“The clinical take-home message is the importance of including the variants of IMP-1, VIM-2 and NDM-1 — along with all the other metallo-beta-lactamases — in the design of inhibitors,” Thomas said.
“The goal is to design a broad-spectrum inhibitor which can be paired with a beta-lactam antibiotic, which would be capable of inhibiting all clinically relevant metallo-beta-lactamases. However, many studies, but not all, focus their efforts toward studying their inhibitors with only NDM-1, VIM-2 or IMP-1,” she said. “I hope that the findings of this study highlight the significance of including variants in the design of inhibitors because metallo-beta-lactamases continue to evolve and pose more of a threat in the clinic.”
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Thomas CA, et al. Using a molecular modeling and native state mass spectrometry quick screening approach to understand the inhibition of IMP-1 variants. Presented at: World Microbe Forum; June 20-24, 2021 (virtual meeting).
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