BARDA Bets on Boron to Bust Bacteria
Sep16

BARDA Bets on Boron to Bust Bacteria

GlaxoSmithKline recently announced a contract with the Biomedical Advanced Research and Development Authority (BARDA), a US government preparedness organization (Note: it’s not often pharma-relevant press releases come from the Public Health Emergency website!). The award guarantees GSK $38.5 million over 2 years towards development of GSK2251052, a molecule co-developed with Anacor Pharma a few years back, as a counter-bioterrorism agent. The full funding amount may later increase to $94 million, pending BARDA’s future option. The goal here is to develop “GSK ‘052”, as it’s nicknamed among med-chemists, into a new antibiotic against especially vicious and virulent Gram negative bacteria, such as the classic foes plague (Yersinia pestis) or anthrax (Bacillus anthracis). So what’s so special about this molecule? Usually, med-chemists “color” with the same atomic “crayons”: some carbon, sulfur, nitrogen, oxygen, and hydrogen, with a few halogens or transition metals every now and then (luckily, the golden age of mercury and arsenic therapies has largely passed on!). But seeing boron ensconced in a lead molecule rings alarm bells . . . you don’t usually see boron in pharmaceutical scaffolds! Look closely at GSK’052 (shown above): that’s a boron heterocycle there! Anacor, a company specializing in boron based lead compounds, first partnered with GSK in 2007 to develop novel benzoxaborole scaffolds. This isn’t the first company to try the boron approach to target proteins; Myogenics (which, after several acquisitions, became Millennium Pharma) first synthesized bortezomib, a boronic acid peptide, in 1995. Stephen Benkovic (a former Anacor scientific board member) and coworkers at Penn State first discovered Anacor’s early boron lead molecules in 2001, with a screening assay. The molecules bust bacteria by inhibiting  leucyl-tRNA synthetase, an enzyme that helps bacterial cells to correctly tag tRNA with the amino acid leucine. Compounds with cyclic boronic acids “stick” to one end of the tRNA, rendering the tRNA unable to cycle through the enzyme’s editing domain. As a result, mislabeled tRNAs pile up, eventually killing the bacterial cell. Inhibition of synthetase function turns out to be a useful mechanism to conquer all sorts of diseases.  Similar benzoxaborozoles to GSK ‘052 show activity against sleeping sickness (see Trypanosoma post by fellow Haystack contributor Aaron Rowe), malaria, and various...

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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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