Mehreteab Mengsteab ACF Abstract FY10

“Effects on substrate selectivity due to Asn152 mutation of P99 cephalosporinase”

Conference Name: Spring 2010/239th National Meeting of the American Chemical Society

Within this past century, medicine has been able to save the lives of millions by effectively putting into use antibiotics based on a ß-lactam core structure. ß-lactam antibiotics combat bacterial infections by disrupting the latter stages of bacterial cell wall synthesis. Over time, bacteria have evolved efficient ways to resist these antibiotics by producing b-lactamase enzymes. These enzymes interfere with ß-lactams by hydrolyzing the lactam ring, thus rendering it inactive. One-way bacteria gain resistance to ß-lactam antibiotics is through new mutations in their beta-lactamase genes. These mutations enable the enzyme to change substrate selectivity, either in addition to or at the expense of the native substrate, thus allowing one ß-lactamase to potentially hydrolyze different ß-lactams. In the enzyme P99 cephalosporinase, mutation of a conserved asparagine residue at position 152 can have a large effect on substrate selectivity.  In this study, a kinetic characterization of N152S mutant was performed. Crystallization efforts are underway. Further studies on the N152S mutant of P99 ß-lactamase may aid in the design of new antibacterial drugs for clinical use.
Mehreteab Y. Mengsteab1, Scott T. Lefurgy2, Virginia W. Cornish3, and Rachel A. Powers1
1Department of Chemistry, Grand Valley State University, Allendale, MI 49401
2Department of Microbiology & Immunology, Albert Einstein College of Medicine, Yeshiva University, 1300 Morris Park Ave., Bronx, NY  10461
3Department of Chemistry, Columbia University, 3000 Broadway, New York, NY  10027

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