Vulnerability found in some drug-resistant bacteria

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A new study analyzing the physical dynamics of all currently mapped structures in an important group of antibiotic-destroying enzymes has found a common structural feature: the physical coordination of a set of flexible components. The apparently universal nature of this complex structural dynamic implies that it is critical to the antibiotic destroying properties of the enzyme and points to the possibility of finding a way to chemically disable the enzymes and bacterial antibiotic resistance, experts say. Using a complex modeling program that helps analyze the physical dynamics of large, structurally complex protein molecules, a research team has made progress towards finding a weak spot in the architecture of a group of enzymes that are essential to antibiotic resistance in a number of bacteria.

In an article published in PLOS ONE, University of North Carolina at Charlotte senior biology major Jenna R. Brown and her faculty mentor, UNC Charlotte professor of bioinformatics and genomics Dennis R. Livesay, present an analysis of the four currently known protein structures of the class C beta-lactamase enzymes — molecular machines that have evolved to allow bacteria to dismantle a variety of antibiotic molecules, including third generation cephalosporins.

The researchers find that all four molecules are remarkably similar in having a rigid protein superstructure, but with three “flexible” structural elements at the active site — the part of the enzyme that acts on the antibiotic. The analysis shows that the flexible structures are “cooperatively correlated” in their motions — the movements of the molecular segments are linked and the linkage is similar in all four molecules analyzed.

The researchers say that the unusual close similarity of the dynamical properties — the way the coupled dynamics within the active site loops is been preserved by the evolutionary process in four different bacterial groups — and the fact that the conserved correlated flexibility happens at the active site implies that this specific structural feature is critical to its advanced antibacterial properties.

“From an evolutionary perspective, this is really cool,” Livesay said. “Here’s a protein that has a very intense set of evolutionary pressures on it, making these couplings critical and not allowing them to vary. We’ve never seen that before. Typically these couplings are quite variable, even when they are otherwise closely related enzymes.” “Clearly this result is important because it is at the active site, because it is evolutionarily conserved, and because we have never seen this degree of conservation in any other system before,” Livesay noted.

The analysis was done using the Distance Constraint Model (DCM), a protein analysis program developed by Livesay and UNC Charlotte biophysicist Donald Jacobs that allows relatively detailed but also relatively streamlined comparison of the properties and behaviors of complex protein structures based on their sequence of amino acids. The DCM’s efficient but accurate structural analysis allowed the researchers to make complex structural comparisons between many different (but related) protein molecules in realistic computing timescales that would be inaccessible by traditional methods. The DCM allows researchers to quickly and accurately pinpoint specific differences in dynamical properties between the structures, such as differing amounts of rigidity/flexibility in specific parts of the protein’s complex structure.  Science Daily  Original web page at Science Daily