Apr. 7, 2000 Almost as soon as penicillin was discovered, more than 70 years ago, certain bacteria had learned how to resist this common antibiotic. These resistant bacteria make beta-lactamase, an enzyme that quickly breaks down penicillin. Now, seven decades later, scientists at the University of Chicago led by Marvin W. Makinen, Ph.D., professor of biochemistry & molecular biology, have discovered exactly how b-lactamases deactivate penicillin.
Their findings, published in the March 28 issue of the journal Proceedings of the National Academy of Sciences, could lead to improved antibiotic design.
"While we cannot predict how these results may lead to improved antibiotics, the chemical principles governing the reactivity of penicillin that we have found are fundamental for designing compounds of pharmacologic importance," says Makinen.
Penicillin-resistant organisms are currently among the most important sources of hospital-acquired infections. Some bacteria have acquired the genetic blueprints for producing a very effective zinc-containing b-lactamase enzyme that is being encountered with increasing frequency in hospitals and in the community.
Makinen and colleagues used analysis of electrostatic forces between individual atoms of the penicillin and b-lactamase enzyme and computational simulation of their interactions. They concluded that b-lactamase attacks penicillin in a way different than previously thought.
An intact penicillin molecule contains a characteristic segment known as the b-lactam ring. Destruction of one crucial bond in the ring causes the penicillin to become deactivated. But instead of the b-lactamase breaking the bond by attacking a key carbon atom that forms part of the bond, b-lactamase destroys the bond by first adding a single proton to it to destabilize it and make it easier to break.
"Knowing more accurately the chemical and physical basis of the interaction of penicillin and b-lacatamses will help in structure-based drug design," Makinen says.
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