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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Forest licenses TransTech’s glucokinase activators
Jun08

Forest licenses TransTech’s glucokinase activators

Interest in glucokinase activators, a class of diabetes compounds with a rocky past, appears to be reviving. Forest Laboratories agreed today to pay $50 million upfront and up to $1.1 billion in milestones for access to TransTech Pharma’s glucokinase activator program. The deal includes the rights to TTP399, which is poised to start Phase II trials, and several other compounds in pre-clinical and Phase I studies. TransTech’s glucokinase activator (GKA) program was developed during a six-year research pact with Novo Nordisk. The Danish firm licensed the program back to TransTech in 2007, when it decided to divest its small molecule drug discovery programs. So what makes glucokinase an interesting diabetes target? A few words on GKAs from our earlier coverage: Glucokinase belongs to a family of enzymes called hexokinases, which catalyze the phosphorylation of glucose to glucose-6-phosphate, a critical first step in metabolizing sugar. Hexokinases are generally marked by their ubiquity—several serve housekeeping functions and are thus found in nearly every tissue in the body—and their tight bond to glucose. But glucokinase is something of a black sheep among hexokinase kin. It is found in relatively fewer tissues, and its affinity for glucose is delicate. In the pancreas it is believed to "sense" just the right concentration of glucose in β cells to signal the release of insulin. And in the liver glucokinase initiates the first step of glucose metabolism, kicking into action after a meal and later sensing when the body is in a fasting state and needs to store glucose. Back when we wrote about GKAs in 2008, several of the companies publicly working on this target talked up the dual roles of glucokinase in the liver and pancreas. While newer diabetes drugs like Merck’s Januvia and Amylin’s Byetta only affect the pancreas, GKAs were expected to have an effect on both organs, improving their control over blood glucose. TransTech, however, is touting the fact that its GKA compounds are “liver selective.” The biggest safety concern with GKAs in development has been hypoglycemia, or low blood sugar. TransTech says that “by activating glucokinase selectively in the liver but not in the pancreas, it may increase glucose utilization and lower blood glucose levels without inducing excessive insulin secretion thus reducing the risk of hypoglycemia.” Interest in glucokinase as a target has waxed and waned. Roche was actively pursuing GKAs not long ago, but a perusal of their public pipeline, which includes multiple diabetes programs,  shows no mention of the target. And a quick look at clinicaltrials.gov shows that Lilly suspended work on its program—licensed from OSI Pharmaceuticals for $25 million upfront in 2007--pending further toxicology testing. Still, late...

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