Jozlyn Clasman

Structural analysis of β-lactamase/drug complexes

OXA-24 is a carbapenem-hydrolyzing class D β-lactamase that poses a serious medical threat by destroying carbapenem class antibiotics.  OXA-160 is a clinically-derived OXA-24 variant with a Pro→Ser substitution.  Previously, it was shown that OXA-160 has higher activity against cephalosporins compared to OXA-24 and maintains activity against penicillins and carbapenems.  To slow deacylation, we introduced a second mutation (Val130Asp) to allow us to capture a drug-complex structure.  We examined OXA-160/Val130Asp in complex with cefotaxime, ceftazidime, and aztreonam using X-ray crystallography.  Our analysis shows that all three of these bulky antibiotics require β5-β6 and/or omega loop deviations, and we propose that these conformational changes are made possible by replacing the restricted proline with the more flexible serine.  These structures reveal that a Pro227Ser mutation enlarges the active site, better accommodating advanced cephalosporin drugs.

Faculty Mentor: Dave Leonard, Chemistry

Page last modified August 2, 2013