MRSA の新規治療標的のような

病院で処方された抗生物質はきっちり飲んでね！というニュースがあっていたところにこの論文です。

PNAS。リポテイコ酸合成酵素の結晶構造解析です・・・アブストのみの感じでは、staphylococci の生育に必要な酵素の結晶構造がわかりました。リポテイコ酸はグラム陽性菌の細胞壁の構成成分なので、LtaS 阻害で新規なクラスの抗生物質にならないかなーというものだと思います。

Structure-based mechanism of lipoteichoic acid synthesis by Staphylococcus aureus LtaS

Proc. Natl. Acad. Sci. Jan.23 2009

Staphylococcus aureus synthesizes polyglycerol-phosphate lipoteichoic acid (LTA) from phosphatidylglycerol. LtaS, a predicted membrane protein with 5 N-terminal transmembrane helices followed by a large extracellular part (eLtaS), is required for staphylococcal growth and LTA synthesis. Here, we report the first crystal structure of the eLtaS domain at 1.2-Å resolution and show that it assumes a sulfatase-like fold with an α/β core and a C-terminal part composed of 4 anti-parallel β-strands and a long α-helix. Overlaying eLtaS with sulfatase structures identified active site residues, which were confirmed by alanine substitution mutagenesis and in vivo enzyme function assays. The cocrystal structure with glycerol-phosphate and the coordination of a Mn2+ cation allowed us to propose a reaction mechanism, whereby the active site threonine of LtaS functions as nucleophile for phosphatidylglycerol hydrolysis and formation of a covalent threonine–glycerolphosphate intermediate. These results will aid in the development of LtaS-specific inhibitors for S. aureus and many other Gram-positive pathogens.

MRSA 関連で構造から創薬の種？のような先行研究はこれですかね。
MRSA の色素の合成酵素 CrtM を阻害することで活性酸素による菌体の除去を促させる？みたいな内容だったかと。

A Cholesterol Biosynthesis Inhibitor Blocks Staphylococcus aureus Virulence

Science 7 March 2008:
Vol. 319. no. 5868, pp. 1391 - 1394

Staphylococcus aureus produces hospital- and community-acquired infections, with methicillin-resistant S. aureus posing a serious public health threat. The golden carotenoid pigment of S. aureus, staphyloxanthin, promotes resistance to reactive oxygen species and host neutrophil-based killing, and early enzymatic steps in staphyloxanthin production resemble those for cholesterol biosynthesis. We determined the crystal structures of S. aureus dehydrosqualene synthase (CrtM) at 1.58 angstrom resolution, finding structural similarity to human squalene synthase (SQS). We screened nine SQS inhibitors and determined the structures of three, bound to CrtM. One, previously tested for cholesterol-lowering activity in humans, blocked staphyloxanthin biosynthesis in vitro (median inhibitory concentration ~100 nM), resulting in colorless bacteria with increased susceptibility to killing by human blood and to innate immune clearance in a mouse infection model. This finding represents proof of principle for a virulence factor–based therapy against S. aureus.

PNAS のほう読んでないんですが、後者はヒトのコレステロール合成系の酵素のひとつと CrtM が似てることに着目したあたりが面白いなーと思います。PNAS も読んでみよう。

標的を変えると、次はどのように微生物が適応してくるのか、これもひとつ興味深い点ではあります。さて明日も頑張っていきましょう。