Event Title
A Pro->Ser Mutation Augments Advanced Generation Cephalosporinase Activity in both the OXA-23 and OXA-24 Beta-Lactamase Subfamilies
Presentation Type
Poster/Portfolio
Presenter Major(s)
Biomedical Sciences, Chemistry
Mentor Information
David Leonard
Department
Chemistry
Location
Kirkhof Center KC 80
Start Date
10-4-2013 12:00 PM
End Date
10-4-2013 1:00 PM
Keywords
Health, Life Science
Abstract
OXA-23 and OXA-24 are class D beta-lactamases that hydrolyze carbapenem antibiotics, thus threatening our ability to treat infection. Fortunately, cephalosporins remain as viable treatment, as these enzymes do not hydrolyze these drugs efficiently. We investigated the properties and structures of two clinical variants containing the same Pro->Ser mutation (in the OXA-23 and OXA-24 backgrounds). Steady-state kinetic measurements show that both variants have much higher affinities for cefotaxime, ampicillin and ceftazidime, while maintaining strong activity toward carbapenems. X-ray crystallographic analysis of OXA-24 P227S reveals that the mutation causes a deviation in a surface loop, enlarging the active site. Models of ceftazidime bound to the variant suggest that this deviation provides room for the binding of the oxyimino side-chain of that drug. These findings warn of emerging class D beta-lactamases that can provide resistance to carbapenems and cephalosporins.
A Pro->Ser Mutation Augments Advanced Generation Cephalosporinase Activity in both the OXA-23 and OXA-24 Beta-Lactamase Subfamilies
Kirkhof Center KC 80
OXA-23 and OXA-24 are class D beta-lactamases that hydrolyze carbapenem antibiotics, thus threatening our ability to treat infection. Fortunately, cephalosporins remain as viable treatment, as these enzymes do not hydrolyze these drugs efficiently. We investigated the properties and structures of two clinical variants containing the same Pro->Ser mutation (in the OXA-23 and OXA-24 backgrounds). Steady-state kinetic measurements show that both variants have much higher affinities for cefotaxime, ampicillin and ceftazidime, while maintaining strong activity toward carbapenems. X-ray crystallographic analysis of OXA-24 P227S reveals that the mutation causes a deviation in a surface loop, enlarging the active site. Models of ceftazidime bound to the variant suggest that this deviation provides room for the binding of the oxyimino side-chain of that drug. These findings warn of emerging class D beta-lactamases that can provide resistance to carbapenems and cephalosporins.