TEDMED: Andrew Read’s Five Tips For Keeping Superbugs At Bay
Apr13

TEDMED: Andrew Read’s Five Tips For Keeping Superbugs At Bay

Researchers may like to think they're pretty smart, but you could argue that bacteria have also got some bragging rights. Every day, microbes develop resistance to even the most powerful antibiotics scientists have developed. Andrew Read thinks evolution is the best lens for staring down the superbugs. He took the stage Thursday at TEDMED, where he warned, "we're picking a fight with natural selection." "Picking a fight without Darwin is like going to the moon without Newton," Read added. "We are in the dark ages when it comes to evolutionary management." Read, director of Penn State University's Center for Infectious Disease Dynamics, sat down with me on Thursday and shared a few principles he thinks the scientific community should keep in mind in order to keep antibiotic resistance in check. Here are his five tips for would-be superbug slayers. Get smart with the drugs you've already got. "We can't rely on a continual supply of new drugs," Read said. Many firms have already exited antibiotic research, he notes. "You can see that the markets aren't good enough right now to drive innovation," since new antibiotics are precious and used only for patients' most severe infections rather than being prescribed widely. Read says firms should continually evaluate dosing and combination strategies with established drugs in order to stave off resistance. "I'm not saying we shouldn't discover new antimicrobials," Read stressed. "In some situations, like malaria, it's really critical. But we don't want to put all our eggs in that basket." Learn from what works. "I think magic bullets are the exception rather than the rule," Read says. But researchers should focus on why wildly successful therapies were so. "Why was that pathogen unable to get around the smallpox vaccine? Why is chloroquine still working against some malarias in some parts of the world when it's has failed miserably in others?" Read asked. Make the right matches for combination therapies. Read notes that some antimalarial drug combinations have consisted of drugs with markedly different half-lives. In effect, once the first drug has left the human body, all that's left is the other drug, a monotherapy. "And that's dangerous," a breeding ground for resistance, Read cautions. "You want to be combining drugs that have similar half-lives." Researchers should also think about whether their antibiotics become more lethal to microbes when used in combination, or less lethal, Read says. Evidence suggests that less lethal is better, he says. According to work from Roy Kishony's lab at Harvard Medical School, if an antibiotic combo is less lethal, once resistance develops to one drug (call it drug A) in the pair, then drug B can...

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Platensimycin On My Mind
Aug10

Platensimycin On My Mind

Yesterday we posted a Latest News item that heralds a potential new class of antibiotics. This is a topic near and dear to my heart, because I worked on the total synthesis of a potential new antibiotic in graduate school. Of course, my time in grad school also taught me not to trumpet 'potential new antibiotics' as the next big wonder drugs, because the molecules in question almost always have yet to be tested in people, a process that seldom goes perfectly smoothly. There was a slightly different twist to this story that made me think it deserved attention: it seems to be nudging researchers and saying, "Don't get so caught up in the hoopla of fancy genomics technology that you ignore old antibiotic targets that still need exploring." In the study, researchers at GlaxoSmithKline, in collaboration with the Wellcome Trust's Seeding Drug Discovery Initiative and the U.S. Defense Threat Reduction Agency, found a small molecule that blocks DNA gyrase, or type IIA topoisomerase, in an entirely new way. The molecule was effective against a panel of drug resistant bacteria and revealed new nuances of the gyrase mechanism to boot. Since the news story discussed revisiting old antibiotic targets, I thought I'd spend some time reminding Haystack readers of a search for a new one. Over the last few years, C&EN has extensively covered the story of platensimycin, a promising antibacterial with an exciting target, first isolated from a South African soil sample. Here's an abbreviated platensimycin timeline: May 2006: Merck researchers report the structure of platensimycin and describe its intriguing activity- it blocks FabF, an enzyme involved in fatty acid synthesis, one that has never before been targeted by antibiotics used in the clinic. October 2006: K.C. Nicolaou group at Scripps Research Institute reports the first total synthesis of racemic platensimycin, setting the stage for making analogs for exploring its bioactivity. April 2008: Lisa Jarvis's C&EN cover story counts platensimycin among the natural product antibiotics in development. March 2009: Microbiologists report that pathogens can scavenge lipids from their mammalian hosts, suggesting that platensimycin's target (part of the lipid synthesis pathway) may not be a viable target for an antibiotic, after all. August 2010: I contacted Merck to ask about the current status of platensimycin. Here is what Dr. Sheo Singh, Merck Research Labs Director of Medicinal Chemistry, who led the discovery team on platensimycin in 2006, had to say: "As part of the merger integration of Merck and Schering-Plough, platensimycin is being evaluated and prioritized along with all the other compounds in the early stage...

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Tetraphase Gets Cash Influx for Antibiotics
Jun01

Tetraphase Gets Cash Influx for Antibiotics

Tetraphase Pharmaceuticals is starting the summer flush with cash after a Series C financing round yielded $45 million. Excel Venture Management led the round. We last checked in with Tetraphase in January, when the company was making the rounds at the JPMorgan Healthcare conference to tout its novel antibiotics platform. Tetraphase was spun out of the labs of Andrew G. Myers, chair of the chemistry department at Harvard University. Myers came up with a fully synthetic route to tetracycline derivatives that significantly expanded the diversity of the compounds. In the past, the semisynthetic routes to make tetracycline limited chemists to making tweaks to the C-7 and C-9 positions on the molecule. Tetraphase’s technology, on the other hand, enables modifications at any position on the molecule. Indeed, their scientists have already made over 2,000 compounds, Joyce A. Sutcliffe, the company’s senior vice president of biology told me. So what does diversity mean in terms of antibiotic activity? Sutcliffe provided the example of Paratek Pharmaceuticals’ PTK0796, a broad spectrum antibiotic that Novartis licensed in October in a deal worth up to $485 million. A modification at the C-9 position of tetracycline endowed PTK0796 with the ability to be given both intravenously and orally—desirable properties when you want to transition a patient from the hospital to home. “It just shows that even small changes make different properties in terms of pharmacokinetics, efficacy, and spectrum,” Sutcliffe said. Now imagine being able to make tweaks at virtually any position on the molecule. Not only can they enable a drug to be taken orally and by IV, but can also improve the activity of the antibiotic. For example, some modifications have proven important to getting around the tetracycline reflux mechanisms, basically the two major pathways bacteria have evolved to pump drugs out of the cell before they can work their magic. Tetraphase will use its sudden influx of cash to push several drugs into Phase I and Phase II clinical trials. TP-434 is a broad spectrum IV antibiotic poised to start Phase II studies this year. Two IV/oral antibiotics, TP-2758 for urinary tract infections and TP-834 for community-acquired bacterial pneumonia, will also be...

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