Antibiotic Faces Uncertain Future

Vol 441|18 May 2006 NEWS Antibiotic faces uncertain future

A promising new antibiotic is generating both excitement and despondency. It is the first new chemical class of antibiotic to be found in more than two decades, but experts fear that the hurdles to turning the compound into an effective commercial drug could mean that it ends up collecting dust on a shelf. The drug, called platensimycin and reported on page 358, kills several of the major drug-resistant bacteria that plague hospitals. Among them are methicillin-resistant Staphy- loccocus aureus (MRSA) and bacteria resistant to vancomycin, one of the last lines of antibiotic defence. Only two other new chemical classes of antibiotic have been discovered and approved for use since the early 1960s: daptomycin and linezolid. Most antibiotics used today were discovered in the 1940s and 1950s, and newer versions have mainly been made by chemically nipping and tucking these compounds. They generally kill bacteria by blocking the production of proteins, DNA or the bacterial cell wall. An antibiotic has been discovered that kills the deadly methicillin-resistant Staphylococcus aureus. Platensimycin has a novel chemical struc- ture and works differently from other com- grow. Two commercially available antibiotics, tories in Rahway, New Jersey, who discovered mercially available antibiotics by crippling triclosan and isoniazid, target another enzyme platensimycin, did so by reviving and tuning FabF, a bacterial enzyme involved in manufac- involved in fatty-acid synthesis, but these do an established strategy. They searched for nat- K. LOUNATMAA/SPL turing fatty acids. It thus stops bacteria from not kill the same array of bacteria. urally existing compounds that microbes typ- making the fatty cell membranes they need to The researchers at Merck Research Labora- ically make to kill neighbouring bacteria. This Neanderthal DNA yields to genome foray

NEW YORK 300,000 to around 30,000 years colleagues used a new sequencing The two are also working to The first nuclear DNA sequences ago, with the first specimen found in technique, developed by 454 Life sequence Neanderthal DNA by the from a Neanderthal (Homo 1856 near Dusseldorf, Germany. Sciences in Branford, Connecticut, traditional method. James Noonan, neanderthalensis) have been Two of the specimens showed that allows genetic fragments in an a postdoc in Rubin’s lab, reported at reported. The results should provide promise, and on 12 May Pääbo’s emulsion to be sequenced directly in the Cold Spring Harbor meeting that clues about when certain diseases, team reported at the Biology of tiny wells. They are now analysing preliminary analysis of the 75,000 or traits such as hair or skin colour, Genomes meeting at New York’s the results to work out how the base pairs sequenced so far shows arose. They also have geneticists Cold Spring Harbor Laboratory that different fragments fit together so that Neanderthals diverged from the excited about the idea of they had managed to sequence that they can be compared with the lineage that led to modern humans sequencing a Neanderthal genome. around a million base pairs of modern human genome sequence. about 315,000 years ago — around Svante Pääbo, a palaeogeneticist nuclear DNA — around 0.03% of One finding so far is that the the time that had been thought. at the Max Planck Institute for the genome — from one of them. Neanderthal Y chromosome is Homo sapiens is known to have Evolutionary Anthropology in This is a 45,000-year-old male substantially more different from evolved at least 200,000 years ago Leipzig, Germany, began his specimen found in Vindija Cave human and chimp Y chromosomes (I. McDougall, F. H. Brown and J. G. Neanderthal Genome Project about outside Zagreb, Croatia. than are other chromosomes. This Fleagle Nature 433, 733–736; 2005). two years ago. He and his team have Typically, DNA to be sequenced suggests that little interbreeding Back in 1997, Pääbo reported probed 60 Neanderthal specimens must be cloned in bacteria to occurred, at least among the more sequencing the first mitochondrial from museums for hints that the produce large enough amounts for recent Neanderthal species. DNA from a Neanderthal (M. Krings DNA might have survived millennia study. But because the Neanderthal Edward Rubin, director of the et al. Cell 90, 19–30; 1997). That of degradation. The species lived DNA had broken down into tiny Joint Genome Institute in Walnut sequence also suggested that across Europe and western Asia from fragments, Pääbo and his Creek, California, works with Pääbo. Neanderthals split from the

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www.nature.com/news S. JUODKAZIS technique originally yielded many potent class against a new target,” says Steven Projan of used sparingly and administered for only a antibiotics, but was abandoned by many drug Wyeth Research in Pearl River, New York. week or two — is small. This has prompted companies as the rate of return diminished But “the next steps are fraught with danger”, many pharmaceutical giants to cut back their and has been replaced by chemical methods to warns microbiologist Carl Nathan of Weill antibiotic research programmes in recent generate novel synthetic molecules. Medical College of Cornell University in New years. Traditionally, researchers have tested York. “The obstacles are truly formidable.” The Merck researchers refuse to spell out whether a tiny amount of chemical can kill off Platensimycin could stumble at one of many their plans for platensimycin, although they a circle of bacteria growing on a plate. But by scientific, regulatory or financial hurdles. One hint that they are working on it. “We are still in first making the bacteria more vulnerable, concern is that it may be unstable in the body, the business of doing antibiotic research, and the Merck researchers searched for natural because the research team had to infuse it con- we wouldn’t be if we didn’t want to develop our products that might have been missed in tinuously into mice to rid them of a S. aureus own compounds,” says Sheo Singh, another of such conventional assays. They engineered infection. The chemical might need extensive Merck’s lead researchers. S. aureus bacteria to make less of the FabF modification to make it more stable, and could Several solutions have been proposed to keep enzyme than normal, using a snippet of RNA prove useless if it has toxic side effects. new drugs flowing into the clinic as micro- to block the production of this protein Testing antibiotics in clinical trials is also organisms overcome old ones. The Infectious (K. Young et al. Antimicrob. Agents Chemother. tough and expensive. This is partly because the Diseases Society of America proposed an array 50, 519–526; 2006). US Food and Drug Administration (FDA) of regulatory measures in 2004 that might The researchers then tested whether any of does not have clear guidelines for approving entice drug companies to develop antibiotics, 250,000 natural-product extracts could block new antibiotics, says Frank Tally, chief scien- such as revised FDA standards for the approval the growth of the disabled strain — and pulled tific officer of Cubist Pharmaceuticals in Lex- of antibiotics and tax breaks for work on such out platensimycin, a small mol- ington, Massachusetts, which drugs (see Nature 431, 892–893; 2004). Some ecule made by a strain of Strep- “Platensimycin’s developed daptomycin. Even if researchers are turning to alternative measures tomyces platensis bacteria in a discovery highlights platensimycin is approved for to fight life-threatening bacteria, such as South African soil sample. “It the fact that human use, it will probably microbe-killing bacteriophage and vaccines. allowed us to find a needle in a meet the fate of its predeces- But many workers still think that novel haystack, and something we compounds are still sors, as bacteria rapidly acquire antibiotics remain the best tried and tested might have missed with waiting to be found.” resistance to it. “It might make way to combat microbes. They say platensi- another type of screen,” says it to the clinic and then fade mycin’s discovery highlights the fact that Stephen Soisson, one of the lead researchers. because of drug resistance,” Nathan says. compounds are still waiting to be found. “With Other scientists are delighted with the new With such a daunting task ahead, some a paper like this, people might start to reinvest compound, and say it could provoke renewed microbiologists fear there is little incentive for in this area,” Tally says, as it shows that interest in natural compounds and in attacking Merck to develop the drug. Not only is the new molecules can be found in well-known the fatty-acid synthesis pathway. “From a scien- process hugely expensive, but the potential sources. ■ tific point of view it is what you want — a new market for a new antibiotic — which is often Helen Pearson

common lineage well before modern the Neanderthals lived. Proving that humans evolved and may not have theory would require finding this contributed any mitochondrial version of the gene in the DNA, at least to modern humans. Neanderthal genome. But the more extensive nuclear Researchers are confident about DNA sequences should pin down the prospects for sequencing much the timing of the split more more Neanderthal DNA. “Our goal is precisely, and comparing genes to sequence a large amount of the for particular traits could help Neanderthal genome,” says Pääbo. researchers work out which That task will probably require characteristics were shared by identifying new fossils. “We should

Neanderthals, and when such traits do it,” agreed Francis Collins, FINNIN/AMNH D. PHOTO & B. MALEY; SAWYER G. J. arose. Such comparisons could also director of the National Human confirm whether Neanderthals did Genome Research Institute, after contribute isolated genes to the attending Pääbo’s lecture on 12 May. human lineage. For example, John Rubin says he envisages creating a Hardy, a geneticist at the National bank of Neanderthal DNA, so that Human Genome Research Institute representative samples can be in Bethesda, Maryland, has compared with the thousands of hypothesized that Neanderthals H. sapiens genomes that are expected may have contributed a gene that is to be sequenced in the future. linked to several neurodegenerative “In ten years, we hope to have ten diseases, because it is found in Neanderthal genomes,” says Rubin.■ people of European ancestry, where Rex Dalton Neanderthal (right) DNA should shed light on the human genome.