Antibiotic-resistant bacteria pose a serious problem in treating infection, with about 2.8 million people diagnosed with resistant bacterial infections in the United States each year, resulting in about 35,000 yearly deaths, according to the Centers for Disease Control and Prevention (CDC). Many research laboratories have worked to develop new inhibitors that inactivate the proteins bacteria use to resist antibiotics such as penicillin and amoxicillin. Researchers from Miami University in Ohio have now optimized a new technique to evaluate how these inhibitors work, and quickly identify best candidates for effective clinical drugs.
The researchers used native state mass spectrometry (native MS) to study how six previously published inhibitors interacted with variations of the bacteria protein metallo-beta-lactamase (MBL), which makes many clinical strains of bacteria resistant to all penicillin-like antibiotics. The native state electrospray ionization mass spectrometry (ESI-MS) technique showed that three out of the six inhibitors were capable of binding to both imipenemase MBL (IMP-1) and a mutated variant IMP-78, while the other three could only bind to IMP-1. The research team’s preliminary molecular modeling suggests a difference in size between the binding pockets of IMP-1 and IMP-73. The study was presented at the American Society for Microbiology World Microbe Forum online conference on June 21, 2021.
“Because metallo-beta-lactamases contain two metal ions we are able to use a variety of spectroscopic techniques to study them,” said Caitlyn Thomas, a Ph.D. candidate in chemistry and presenting author of the study. “These experiments give us more insight into how the inhibitor behaves and whether it could potentially be a candidate for clinical use in the future.”
The team plans to perform more tests using native MS to better understand the mutations that prevent inhibitor binding to IMP-73 as compared to IMP-1 and other variants.