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Title: Structural and functional characterization of methicillin-resistant Staphylococcus aureus’s class IIb fructose 1,6-bisphosphate aldolase

Staphylococcus aureus is one of the most common nosocomial sources of soft-tissue and skin infections and has more recently become prevalent in the community setting as well. Since the use of penicillins to combat S. aureus infections in the 1940s, the bacterium has been notorious for developing resistances to antibiotics, such as methicillin-resistant Staphylococcus aureus (MRSA). With the persistence of MRSA as well as many other drug resistant bacteria and parasites, there is a growing need to focus on new pharmacological targets. Recently, class II fructose 1,6-bisphosphate aldolases (FBAs) have garnered attention to fill this role. Regrettably, scarce biochemical data and no structural data are currently available for the class II FBA found in MRSA (SaFBA). With the recent finding of a flexible active site zinc-binding loop (Z-Loop) in class IIa FBAs and its potential for broad spectrum class II FBA inhibition, the lack of information regarding this feature of class IIb FBAs, such as SaFBA, has been limiting for further Z-loop inhibitor development. Therefore, we elucidated the crystal structure of SaFBA to 2.1 Å allowing for a more direct structural analysis of SaFBA. Furthermore, we determined the KM for one of SaFBA’s substrates, fructose 1,6-bisphosphate, as well as performedmore » mode of inhibition studies for an inhibitor that takes advantage of the Z-loop’s flexibility. Altogether the data offers insight into a class IIb FBA from a pervasively drug resistant bacterium and a comparison of Z-loops and other features between the different subtypes of class II FBAs.« less
Authors:
 [1] ;  [1] ;  [1] ;  [1] ;  [2]
  1. Univ. of Denver, Denver, CO (United States)
  2. Univ. of Georgia, Athens, GA (United States)
Publication Date:
Grant/Contract Number:
AC02-05CH11231
Type:
Published Article
Journal Name:
Biochemistry
Additional Journal Information:
Journal Volume: 53; Journal Issue: 48; Journal ID: ISSN 0006-2960
Publisher:
American Chemical Society (ACS)
Research Org:
Univ. of Denver, Denver, CO (United States); Univ. of Georgia, Athens, GA (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); USDOE Advanced Research Projects Agency - Energy (ARPA-E)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES
OSTI Identifier:
1164331
Alternate Identifier(s):
OSTI ID: 1345591