2011年12月7日水曜日

薬剤耐性菌研究発表

薬剤耐性菌の研究が報道された。

大阪大産業科学研究所の山口明人教授らグループ
・細菌の表面にある細胞膜に、薬を異物と認めて外にはき出す働きをする
 たんぱく質があるのを見つけ、その構造を研究。
・たんぱく質には、薬がくっつく部位が2種類あることを新たに確認。
 各々複数の「鍵穴」があり、その組合せによって、多様な薬を異物とし
 て見極めている。

Brown University
・細菌が抗菌薬をはき出すため、抗生物質に影響受けやすくする合成薬を
 開発。
・細菌が抗菌薬(chloramphenicol)をはき出す働きがあるため、抗生物質の
 影響を受けやすくするために、はき出す働きを止める合成薬(BU-005)を
 開発。

報道記事から推察すると、大阪大学は、抗菌剤を排出する仕組みを見つけ
たが、ブラウン大学は、排出させない仕組みができたと言うことだろうか。
詳細は不明。

MPEX Pharmaceuticals社、RND型薬剤排出ポンプを止める薬を開発し、
FDAの臨床試験フェーズIを実施中とのこと。

細菌は、一つの遺伝子で5-6の耐性を持つことができるらしい。
薬剤耐性菌研究は、より強く高価な抗生物質を開発するか、細菌のはき
出す機能を研究する方法が主だったようだ。細菌のはき出す機能の研究
が進めば、多くの耐性菌の問題は解決できるかもしれない。
臨床試験が終了し、一般販売になった時に、副作用が少なければ良いと
思う。

多剤耐性菌 国内定着か
抗生物質のない世界の終末シナリオ
薬剤耐性淋菌


---多剤耐性菌の「耐性」ナゾ解明 阪大、治療薬開発へ一歩---
2011年11月29日8時26分
http://www.asahi.com/science/update/1128/OSK201111280015.html

 多くの抗生物質が効かない「多剤耐性菌」は、何種類もの薬をどのように認識してはねつけるのか。そのしくみを大阪大産業科学研究所の山口明人教授らのグループが解明した。細菌の耐性化を防ぐ治療薬の開発につながると期待される。28日付の英科学誌ネイチャーに掲載された。
 グループは、細菌の表面にある細胞膜に、薬を異物と認めて外にはき出す働きをするたんぱく質があるのを見つけ、その構造を研究してきた。今回、このたんぱく質には、薬がくっつく部位が2種類あることを新たに確かめた。それぞれに複数の「鍵穴」があり、その組み合わせによって、多様な薬を異物として見極めているという。
 山口さんは「細菌が異物を排出するしくみの全容が見えた。耐性菌ができないような、分子標的タイプの抗生物質を開発したい」と話す。(権敬淑)


---New Compound Defeats Drug-Resistant Bacteria---
Nov. 28, 2011
http://www.sciencedaily.com/releases/2011/11/111128132706.htm

ScienceDaily (Nov. 28, 2011) - Chemists at Brown University have synthesized a new compound that makes drug-resistant bacteria susceptible again to antibiotics. The compound -- BU-005 -- blocks pumps that a bacterium employs to expel an antibacterial agent called chloramphenicol. The team used a new and highly efficient method for the synthesis of BU-005 and other C-capped dipetptides.

Results appear in Bioorganic and Medicinal Chemistry.

It's no wonder that medicine's effort to combat bacterial infections is often described as an arms race. When new drugs are developed to combat infections, the bacterial target invariably comes up with a deterrent.

A particularly ingenious weapon in the bacterial arsenal is the drug efflux pump. These pumps are proteins located in the membranes of bacteria that can recognize and expel drugs that have breached the membranes. In some cases, the bacterial pumps have become so advanced they can recognize and expel drugs with completely different structures and mechanisms.

"This turns out to be a real problem in clinical settings, especially when a bacterial pathogen acquires a gene encoding an efflux pump that acts on multiple antibiotics," said Jason Sello, assistant professor of chemistry at Brown University. "In the worst case scenario, a bacterium can go from being drug-susceptible to resistant to five or six different drugs by acquiring a single gene."

A new way to attack drug-resistant bacteria: "If drug efflux pumps are inhibited, then bacteria will be susceptible to drugs again."That leaves two choices: Make more new and costly antibiotics or find a way around the pump. Sello and his group chose the latter. In a paper published in the journal Bioorganic and Medicinal Chemistry, the team reports it has discovered a new compound of C-capped dipeptides, called BU-005, to circumvent a family of drug-efflux pumps associated with Gram-positive bacteria, which include the dangerous MRSA and tuberculosis strains. Until that discovery, C-capped dipeptides were known to work only against an efflux pump family associated with Gram-negative bacteria.

"If drug efflux pumps are inhibited, then bacteria will be susceptible to drugs again," Sello said. "This approach is of interest because one would have to discover efflux pump inhibitors rather than entirely new kinds of antibacterial drugs."

Recently, a company called MPEX Pharmaceuticals discovered that specific C-capped dipeptides could block the efflux pumps of the RND family, which are responsible for much of the drug resistance in Gram-negative bacteria. One of these compounds developed at MPEX advanced to phase I of an FDA clinical trial. Sello and his co-authors investigated whether C-capped dipeptides could block the pumps of another drug efflux family, called the major facilitator superfamily (MFS), which is associated mostly with Gram-positive bacteria.

The Brown team thought that new and perhaps more potent C-capped dipeptide efflux pump blockers could be discovered. Since it is not possible to predict which C-capped dipeptides would be efflux pump blockers, they synthesized a collection of structurally diverse C-capped dipeptides and screened it for compounds with new or enhanced activities.

Normally, this is a four- to five-step process. Sello's group reduced that to two steps, taking advantage of a technique used in other chemistry practices, known as the Ugi reaction. Using this approach, the team was able to prepare dozens of different C-capped dipeptides. They assessed each compound's ability to block two efflux pumps in the bacterium Streptomyces coelicolor, a relative of the human pathogen Mycobacterium tuberculosis and which resists chloramphenicol, one of the oldest antibacterial drugs.

From a collection of nearly 100 C-capped dipeptides that they prepared and tested, the group discovered BU-005. The new compound excited the researchers because it prevented the MFS efflux pump family from expelling chloramphenicol. Until now, structurally related C-capped dipeptides had only been reported to prevent chloramphenicol expulsion by other drug efflux pump families.

"Our findings that C-capped dipeptides inhibit efflux pumps in both Gram-positive and Gram-negative bacteria should reinvigorate interest in these compounds," Sello said. "Moreover, our simplified synthetic route should make the medicinal chemistry on this class of compounds much simpler."

Two Brown undergraduate students, Daniel Greenwald '12, and Jessica Wroten '11, helped perform the research and are contributing authors on the paper.

Greenwald joined the team in his freshman year, after reaching out to Sello. "This project was the first real immersion I had into chemistry research at an advanced level," said Greenwald, of Madison, Wisc. "It was an amazing opportunity to be able to use the tools of synthetic chemistry to address problems from molecular biology. It was definitely one of the most engaging aspects of my experience at Brown."

Babajide Okandeji, who earned his doctorate last May and is a new products quality control chemist at Waters Corp. in Taunton, Mass., is the paper's first author.

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