Front-line Antibiotics To Fight E. Coli
Jun17

Front-line Antibiotics To Fight E. Coli

Guest blogger SeeArrOh comments on the limited chemical weapons available to treat E.coli and its Gram-negative brethren.  SeeArrOh is a Ph.D. chemist working in industry. Yesterday’s post at In the Pipeline asking what kind of translational research should be done garnered some remarks about the importance of developing antibiotics for Gram-negative bacteria. It’s a timely appeal, because this May an especially virulent strain of the Gram-negative microbe E. coli, named O104:H4, was discovered in Germany. As reported by the Robert Koch Institute, the German equivalent of the CDC, the outbreak has (to date) killed 35 people and sickened more than 3,200. This deadly strain produces Shiga toxins, which target the kidneys, causing hemolytic-uremic syndrome, a disease characterized by red blood cell death, low platelets, anemia, and  kidney failure. These outbreaks are not uncommon, as bacteria constantly evolve and adapt. So, when a superbug strikes, why don’t we have anything better to fight it with? Vaunted antibiotics vancomycin and the methicillin derivatives won’t hinder E. coli, since they are designed to stop a different type of microbe – Gram-positive, such as Staphylococcus or Pseudomonas.  E. coli's Gram-negative classification means that a fundamental difference in their cell walls lends them protection against certain antibiotics.  The fast reproduction rate of most bacteria, coupled with selection pressure from inhospitable environments (like new drugs), drives them to resistance even faster. Of course, we kill millions of E. coli all the time with common antibacterials: triclosan, a chlorophenol found in soaps and hand sanitizers, inhibits fatty-acid biosynthesis in both bacterial subtypes. Neosporin, familiar to many a scraped knee, contains two Gram-negative bactericides: neomycin sulfate and polymyxin B. To counter the tougher stuff, the front-line therapy against hospital-based E. coli infections has been the carbapenem antibiotics. These are extensions of the penicillin β-lactam motif, substituting sulfur for carbon, and are active against most strains of E. coli. Meropenem, first approved in 1996, was one of the first of this class, showing activity against abdominal and skin infections. Unlike penicillin, most carbapenems don’t reach the bloodstream efficiently when they are taken orally, which can limit their application. Though carbapenems may be strong antibiotics, E. coli fights back: in 2008, a bacterial enzyme was identified in E. coli taken from a patient traveling from India to Sweden, which granted resistance to the carbapenems.  This enzyme, better known as NDM-1 (New Delhi metallo-beta-lactamase-1) has the power to cleave the β-lactam bond found in most penicillin-derived compounds, thus rendering them non-lethal to the bacterium. So far, the NDM-1 variant has been found in the US, Canada, Japan, Brazil, Afghanistan, Australia, the UK, and India. Thanks to horizontal gene transfer, where...

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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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