Small molecules that modulate quorum sensing

On Thursday Helen Blackwell from the University of Wisconsin Madison braved the cornfields and soybeans that pave the way south to the U of I and gave an awesome seminar. Unfortunately I didn't get to go out to lunch with her, but several other members of my group did. From what I hear, she is quiet, witty, observant, and very interested in hearing what students have to say. Although I was a little disappointed that she didn't mention much about her group's work on small molecule macroarrays, she did discuss their recent article on quorum sensing in Vibrio fischeri, which is a fascinating story for anybody interested in chemical biology. She even satisfied those hard-core organic chemists with some microwave assisted reactions. If I remember correctly, they have been able to reduce the reaction time from 24-48 hours to under 30 minutes for the final cyanogen bromide mediated cyclization step in the synthesis of N-phenylacetanoyl-L-homoserine lactones. Pretty amazing what microwaves can do.

Bacteria are able to control their population growth through a process called quorum sensing. By releasing certain molecules into their media, bacteria can signal to each other and thus are able to alter their mode of growth; essentially this communication allows them to function as muticellular communities rather than single celled organisms. Gram negative bacteria are known to use N-acylated-L-homoserine lactones (AHLs) for communication. Previous studies have shown that phenylacetanoyl-L-homoserine lactones (PHLs) can act as antagonists of quorum sensing, so Blackwell and coworkers created a small library of PHLs and tested their activity in the bioluminescent bacteria Vibrio fischeri. While this library contained less than 30 compounds, it included some of the best antagonists AND agonists of gram-negative bacteria that are known to date. Very small structural changes elicited huge differences in activity.

In my opinion, one of the most interesting points of the talk was Blackwell's discussion of the Hawaiian bobtail squid. Apparently its light organ (which is used for hunting and prevents the squid's shadow from alerting potential predators/prey to its position) is inoculated with V. fischeri shortly after birth. Quite an interesting symbiotic relationship--the squid provide the bacteria with a home and food source in exchange for light. Blackwell shared some preliminary data with us indicating that the superagonist discovered in the small PHL library is well tolerated and active in vivo. The juvenile squid utilized for these experiments are tiny enough to fit into the wells of a 96-well plate, and in my opinion they are very cute (as illustrated by the picture above, V. fischeri image from Geske, G.D. ; O’Neill, J.C.; Blackwell, H.E. (2007) ACS Chemical Biology 2(5), 315-320.).

Binding DB

As brought to my attention by my PI--the Gilson lab at the University of Maryland Biotechnology Institute has been working to develop a database of known protein-ligand binding affinities, also known as the BindingDB. While the BindingDB currently contains only about 15,000 small molecule ligands and 30,000 affinities to proteins measured through isothermal titration calorimetry (ITC) and enzyme inhibition methods, the database is rapidly increasing in size, at a rate of about 10,000 new data points per year.

You can search for your favorite protein or ligand, but there are also several other search features such as molecular weight, K_i, and substructure. Users are encouraged to deposit data from their own published binding experiments, so hopefully this database will continue to grow in the future. Once enough information has been collected, I can imagine that the BindingDB will become a powerful tool in drug discovery--Not only can you download computer models of compounds and affinity measurements, but there is also an interesting virtual screening section of the website that I'd like to explore when I have some spare time.

Of course, this isn't the only database that characterizes molecular interactions. Some of the others include:

• Database of Interacting Proteins (DIP)
• Protein-Nucleic Acid Interactions (ProNit)
• K_iBank
• PDBBind Database
  

Ocean breeze...

While I've always thought the smell of the ocean was quite a pleasant one, I'm apparently mistaken. According to Andrew Johnston and coworkers, dimethyl sulfide (DMS) is the major form of sulfur released from aquatic environments and contributes highly to the distinctive smell of the ocean. Honestly, I've smelled a bottle of DMS before and the thought of comparing its smell with that of a gentle sea breeze never crossed my mind. Production of DMS in the oceans stems from dimethylsulfoniopropionate (DMSP), which is a metabolite produced by seaweed phytoplankton, seaweed macroalge, and salt marsh grasses. During times of stress (like those times you come back from the beach looking worse than a lobster, when the UV-index is extremely high) plankton release DMSP, which is subsequently catabolized into DMS. One of cool fact--oxidation products of DMS are known to seed clouds--so do these creatures purposefully secrete DMSP to generate clouds and thus protect themselves from the sun's harmful rays? Something tells me that this is not the case, but it is interesting to consider nonetheless. DMS production protects cells from ROS and has been shown to prevent some kinds of viral infections in algae, and these are the more likely reasons for DMS synthesis. A potential downside of DMS production for these creatures?? They get eaten. Both crustaceans and birds are known to be attracted to its smell as it serves as a chemical indicator for food[1],[2],[3].

Note: Be sure to check out the "CLAW hypothesis" if you've never heard of it before...

Idea Generator

Not related to chemistry, but worth the visit.