Bacteria

I didn't even think of this one and I think about germs a lot. A research team in Colorado has shown that there are bacteria present on our shower heads that could negatively affect those with compromised immunities. This study examined 45 showers in hotels and random houses in various cities. Specifically, the researchers found 100 times more mycobacterium avium, a gram positive mycobacteria, shown on the right, in the water coming out of the shower head than in the water coming into it. Bacteria are classified based on a couple of characteristics, including their ability to absorb a stain called Crystal Violet. The majority of harmful bacteria can not retain this purple stain and are called gram negative. Those in good health should not worry about this germ filled study but those already sick should stick with metal shower heads, as they are less likely to breed bacteria than.

Now bacteria are not all bad. Professor van der Donk at the University of Illinois at Urbana-Champagne is using these tiny organisms to search for compounds that can kill other bacteria. This seems counter intuitive, why would bacteria make antibiotics? Indeed a gram positive bacteria, Lactococcus, is one of many bacteria that produce bacteriocins or toxins that inhibit the growth of similar bacteria. It seems it might help to be the only bully on the block. This is great for us because we can use these bacteria to identify new compounds that are medicinally relevant and most importantly have very creative structures. Nisin, shown on the right, is made by an enzyme in Lactococcus in two steps. While humans have been able to make Nisin in the lab in something like 70 steps. The neat thing about this molecule is that it has been used as an antibacterial in processed food for over 40 years. No resistance has been seen. This is amazing considering the amount of bacterial resistance that we are dealing with in the medical community. Currenlty, the researchers are exploring the relevant chemistry of this compound in order to understand how to make better antibiotics and also to perhaps harness some of these bacterias to make these antibiotics for us.

A joke at every end:

A man is pulled over for driving all over the road.
The cop, suspecting the driver of drinking, walks up to him and says "sir you are going to have to take a breathalyzer test."
"I can't do that," the man responds, "I have asthma and I might start coughing and die."
"Well we have an urine testing kit to measure alcohol level in the back," says the cop."So why don't you pee in a cup for me."
The man says, "I can't do that. I am a diabetic and if I pee I will lose too much sugar, faint, and die."
The cop says, "well then you are gonna have to go the station so we can draw some blood."
The man responds, "well I definitely can't do that. I am a hemophiliac and if I give blood I'll bleed everywhere and die."
"Fine" the cop says, "just get out of the car and walk in a straight line for me."
"I can't do that either," says the man.
"And why the hell not," asks the cop.
"Cause I am drunk," says the man.

Reinventing Drug Developement

One of the big challenges in front of the chemical community is to reinvent drug development as we know it. A really cool professor at the University of Michigan named Jason Jestwicki published a research paper in 2009 describing one such approach. His stated goal was to stop cytochrome p 450 from metabolizing an HIV protease inhibitor called amprenavir (right). GlaxoSmithKline, the company producing the drug, has dealt with the metabolism problem by distributing the medication in its prodrug form, fosamprenavir (left - note the addition of the phosphate group in the middle of molecule). The prodrug, digested in the body into the active ingredient, increases the absorption and distribution of amprenavir. Professor Jestwicki, instead of adjusting smaller functional groups, looked to nature as inspiration. Tacrolimus, or FK-506 (lower right), was discovered in soil fungus in 1984. FK-506 is a potent immuno suppresant but defies certain expected drug like properties that have been established over the years. For example, it is bigger and has more hydrogen bond donors and acceptors then the majority of FDA approved drugs. After some work, it was shown that FK-506 accumulates in whole blood by binding to a cellular receptor, FKBP. By hiding in the cellular part of whole blood, FK-506 avoids Cytochrome P450 all together. So Professor Jestwicki tethered the FKBP binding functional group to amprenavir (picture available through the pubmed link above) and created a drug that so far has had a half life of 50 hours in vivo as compared to 7-8 hours for fosamprenavir and 80 fold increase in activity.

The critical element to this study is the thought process behind it. Instead of manipulating well developed and understood chemistry that has historically improved bioavalibility, Jestwicki's group utilized a technique from a drug that seemingly has nothing to do with HIV treatment.

Looking over this novel strategy to fight disease I can't help but imagine a place far away where all diseases have their laboratories. A place where graduate students in diabetes and HIV work together to improve resistance to available medication. Where yearly conferences feature cancers and flu viruses on the same panel because they both have figured out a way to utilize genetic variation to survive. We have come to a point in time where we need to look beyond improving target based therapeutics for each particular disease. The method of success inherent to one therapeutic needs to be categorized and applied to as many diseases as possible. The Jestwicki lab identified one such opportunity by connecting HIV medication and an immuno suppressant. We need to have our pro-health graduate students studying cancers and flu talk together and share their methodology for that might be the key for better drug development.

A joke at every end:

A physicist, biologist, and chemist are sitting on the beach and watching the water.
All of a sudden the physicist can't take it anymore and yells "I have to go examine the sine and cosine curves in those waves!" He runs into the water and drowns.
Next the biologist jumps up and yells "I have to go examine the marine life in this ocean!" He runs into the water and drowns.
Finally, the chemists looks up and says "oh look physicists and biologists are water soluble."

artemisinin

Fig. 1, Artemisinin

This is a historical molecule. The first use of the tri-cyclic peroxy like (two oxygen atoms bonded to each other) structure was noted in 200 BC. Throughout the past 2000 years, Chinese herbalists used the plant from which this molecule derives, Artemisia Annua, for various maladies.

In the 1960s and 1970s the Chinese government established a program exploring the use of some 200 traditional herbs for the treatment of the growing threat of Malaria, a disease most commonly caused by an infection of a parasite called Plasmodium falciparum. Out of those trials, artemisinin was the only one that was turned into a drug.

Artemisinin has an unusual structure for a drug like compound. The double oxygen peroxy group is not very stable. Indeed, the poor bioavalability has to be offset through combination therapies. Derivatives such as artesunate (below, note the extra 4 carbon tail) have also been used as alternative, longer lasting treatments.

Fig. 2, Artesunate

As a side note, this 4 carbon tail is a functional motif found in some hdac inhibitors such as sodium phenylbutyrate and a recent breakthrough drug, vorinostat or SAHA. The side chain increases the hydrophybicity of the molecule and perhaps makes a better binding partner to cellular targets.

Fig. 3, Sodium Phenylbutyrate
Fig. 4, Vorinostat - note the form of the carbon chain

The mechanism of action for artemisinin is not clear, but it seems that the peroxide group is broken by free heme groups that are released by parasitic digestion of hemoglobin.

Recently, the HHV-6 Foundation, a not for profit organization exploring the role of the Human Herpes Virus 6 (HHV-6) in various diseases, has started funding a project to explore the use of artesunate for HHV-6 infection. It is very intriguing that a drug that has been used to disrupt a parasitic infection might also be effective against a viral infection.

There is much more to explore in a post about artemisinin. There are fears right now that monotherapy in third world countries, with artemisinin or its derivatives, is leading to resistance in Plasmodium falciparum. Separately, the synthesis of artemisinin is an important challenge as the extraction and growth of the plant source is impractical to treat the large number of people afflicted by malaria.

A joke at every end:

What do you call a sheep with no legs?
A cloud.