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The Kinetic Studies of saFabI, the Enoyl ACP Reductase From Staphylococcus aureus
Author(s) -
Xu Hua,
Sullivan Todd,
Kirikae Teruo,
Tonge Peter J.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a999-c
Subject(s) - staphylococcus aureus , enzyme , reductase , microbiology and biotechnology , chemistry , antibiotics , biochemistry , bacteria , stereochemistry , biology , genetics
Methicillin‐Resistant Staphylococcus aureus (MRSA), is a huge concern in the United States, since one in twenty Americans contract MRSA infection while in hospital. In addition, the recent emergence of MRSA strains that are resistant to all current antibiotics, has caused a further increase in the pressing need to discover new drugs against this organism. Our studies are focused on saFabI, the enoyl ACP reductase from Staphylococcus aureus, which is a validated target for drug discovery. Fatty acid biosynthesis is essential for bacterial survival, and we are currently investigating the enzymatic mechanism of saFabI as a prelude to the development of potent inhibitors of this enzyme. Results from kinetic studies reveal that saFabI is an NADPH‐dependent enzyme, and that substrate reduction proceeds via a random ternary complex mechanism. Selection for resistance to some of our diphenyl ether‐based enoyl reductase inhibitors suggests that 5‐chloro‐2‐phenoxy‐phenol and 5‐ethyl‐2‐phenoxy‐phenol target saFabI within the bacterium. These compounds are slow binding inhibitors of saFabI, and currently we are quantitating enzyme inhibition using progress curve analysis. We are also in the process of determining the structure of saFabI in complex with the diphenyl ether inhibitors and are evaluating the effect of mutations on enzyme activity and inhibition.