Category: Chemistry

The authors of a paper published in this week’s Nature claim to have srtuck a blow against the rising tide of antibiotic resistance. Jun Wang and colleagues at Merck’s Research Laboratories, in Rahway, New Jersey, have found a potent antibiotic from a microbial fungus, which they demonstrate kills many Gram-positive bacteria, including the current media darlings methicillin-[or multiple]-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE).

The new antibiotic, platensimycin, was just one of 250,000 natural product extracts they screened from a strain of the South African soil microbe Streptomyces platensis.

What makes platensimycin so interesting is its mode of action, which is completely different from any other antibiotic. This compound kills bacteria by blocking the enzymes involved in the synthesis of fatty acids, the building blocks of lipids. No existing antibiotics target fatty-acid synthesis in this way. The antibiotic clears Staph infection without any apparent side effects and it or an analog is now very likely to be pursued by the pharmaceutical industry.

Only two new classes of antibiotics have been found since the mid-1960s, the linezolid type (oxazolidinones) and daptomycin (lipopeptide), most of the others we use were found in the 1940s and 1950s and target specific bacterial biochemical processes, such as cell wall construction, their DNA and proteins. This limited arsenal allowed bacteria to evolve resistance to pretty much every antibiotic, which is why a new class is so keenly sought.

According to Eric Brown of McMaster University, in Hamilton, Ontario, “The report reads like a textbook of modern antibacterial drug discovery, beginning with a screen of 250,000 extracts from drug-producing microorganisms. What follows is a series of elegant studies, spanning bacterial genetics, biochemistry, pharmacology and structural biology, and leading to the discovery of a small molecule.”

Ever the cynic I cannot help worry that regardless of how novel this compound is at this point in its clinical history, as with all of its predecessors, bacteria are likely to evolve just as effective defences as their cousins once we begin to use platensimycin in medicine. That was the lesson we should have learned the very first time the prototypical antibiotic penicillin was used! Today’s wonder drug quickly becomes tomorrows acronym, give it a few years and the headlines will be screaming about PRSA, you can bet on it.

Nature, 2006, 441, 358

The decline in UK chemistry departments has been staved off at least partially with a vote to save the department a Sussex University on the south coast that spawned two Nobel chemists.

According to The Guardian, ‘The University of Sussex has abandoned its controversial plans to axe its chemistry department following intense criticism from scientists across the country.’

Vice-chancellor, Alasdair Smith, originally suggested chemistry teaching be scrapped and a new bio-merged department take its place, but, the paper reports that an extraordinary university council meeting held on May 15 saw members adopting a recommendation that will see the incredibly well-respected department retained and expanded to include biochemistry.

Sussex has produced two Nobel chemists Sir John Cornforth (1975, for stereochemistry of enzyme-catalyzed reactions) and Sir Harry Kroto (1996 winner for fullerene co-discovery) with a former professor of physics, Anthony Legget, being awarded a share of the 2003 Nobel Prize for Physics, for his work at Sussex on the theory of superfluids.

Taxol is a natural product isolated from the Pacific Yew, Taxus brevifolia. The compound was isolated from the bark of that tree by Monroe Wall of the Research Triangle Institute in the 1960s. He and his colleagues were guided in their work by the discovery of in vitro activity against L1210 cancer cells.

As is customary, the individual who discovers a new natural product gets to name that compound. Wall thus naturally called this new anticancer agent taxol (tax from taxus, ol as in alcohol, small T). He used the name in his 1971 publication announcing the chemical structure.

After that, chemists working with the compound used this name, partly because its very complex structure virtually precluded using the systematic chemical name.

Probably because it was so hard to obtain it in quantity, the compound lay fallow on a shelf at NCI until the late 1980s. Interest was revived when Susan Howrwitz discovered that the drug acted by a previously unknown mechanism: in essence it freezes cell division mid-stream by stabilizing the microtubules that should wither after pulling appart the pieces of the cells-to-be. The late Matt Suffness at NCI then made a concerted effort to pursue the compound. As part of this, NCI apparently requested bids from the private sector to join in developing taxol as an antitumour drug. This was to be one of the first such joint efforts known by the acronym CRADA (Cooperative Research And Development Agreement). The proposal tendered by Bristol Myers was deemed to be superior to the others leading to the company being awarded the agreement. The rest as they say, is history.

Somewhere along the line, however, someone either forgot to register the name taxol with the USAN as the non-proprietary name for that substance or may simply have been unaware of this requiremnent. This left the door open for Bristol Meyers to acquire Taxol as a trade name allegedly via the purchase of the TradeMark of an old laxative product and to have the non-proprietary name paclitaxel accepted as the generic term of Taxol. This meant that chemists would no longer be allowed to talk of taxol generically but would have to refer to paclitaxel, unless they were talking about BM’s drug in which case that would be Taxol, with a capital T.

So what of this laxative? It was apparently produced by Continental Laboratories Ltd of London in tablet form for the physiological treatment of constipation.

One further thought on the benzene soft drinks story following on from sciencebase reader Ross Getman’s comment…

Bob Buntrock (of Louisiana State University) on the CHMINF-L discussion group mentions the recent C+EN article on this issue, (Dispute Over Benzene In Drinks, Bette Hileman, Chemical and Engineering News, 84(17), April 24, 2006).

Buntrock points out that when tests were carried out again in 2005, they revealed a very different picture of benzene levels than before. Apparently, previous tests by the FDA showed that almost four out of five beverages tested, even after “reformulation”, had benzene levels greater than 5 ppb, the US standard for tap water. The latest (preliminary) tests showed no benzene or levels less than 5 ppb.

“Since the first method involved heating samples at 100 Celsius for 30 minutes(!) [His exclamation] and the latest method uses headspace methodology “which does not involve much heat”, guess which method would appear to be more accurate,” says Buntrock. In his opinion, “considerably more decarboxylation of many acids or carboxylates will occur under the previous drastic conditions, which are extremely unlikely to occur under normal usage of soft drinks.”

Jacob Zabicky of Ben Gurion University, Israel, followed up Buntrock’s comment with a remark based on knowledge of the physical properties of benzene. “My gut feeling based on the relative solubility of benzene in water and its volatility from solution at ppb levels,” he said, “is that if there is any ppb level benzene at the start it will go with the fizz.” On the basis of the Henry Constant of benzene in water, Zabicky adds that, “The given value means that for every four molecules dissolved in a given volume of water one molecule of benzene is found in the same volume of headspace in equilibrium.” In other words if the headspace volume is large (i.e. the air above a drinks can as it is opened) compared to the volume of soft drink, then the benzene will be strongly depleted from it.