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 bacteria eject tiny fragments of their DNA for other bacteria to scoop up and incorporate into their own genes, scientists have found NDM-1 in multiple other species besides E. coli, including Salmonella and K. pneumoniae.
The broad-spectrum fluoroquinolone antibiotics, such as ciprofloxacin (better known by its brand name Cipro), are the go-to for most international travelers to treat food poisoning, most commonly caused by unfamiliar E. coli ingested in foreign foods. In fact, Cipro has become a veritable blockbuster drug, first breaking a billion dollars per year in sales in 1999. The popularity had a price: bacterial resistance to Cipro was already noted in 2001. Cephalosporins, such as the fourth-generation drug Cefepime, also show high activity against resistant Gram-negative bacteria. However, resistance to cephalosporins in animal populations showed up as early as 2000. In late 2010, Forest Laboratories, a New York based pharmaceutical company, released Teflaro (ceftaroline fosamil), a later-generation cephalosporin for the treatment of skin infections and pneumonia, which shows activity against E. coli, strep, and staph, among others.
Do we have any other drugs coming down the pipeline? CNN, in an interview with Dr. Helene Boucher, director of the Infectious Diseases Fellowship Program at Tufts Medical Center and lead author for the Infectious Diseases Society of America report on Gram-negative bacteria reported two years ago, “there has been an increase in infections caused by Gram-negative bacteria, and they are resistant to many, or sometimes all, drugs [and] there is no antibiotic drug in Phase II or beyond, in patients.”
The government’s trying to fix the situation. Pharmalot reported yesterday that a bill to offer incentives to drugmakers that develop antibiotics for stubborn infections was reintroduced in Congress.
And Lisa Jarvis, of C&EN and The Haystack (this very blog!) wrote several pieces in 2008 about small companies trying to fill this niche: Replidyne, Optimer Pharmaceuticals, Paratek, Targanta Therapeutics, and Cubist. Of these, several have taken serious steps to supplement their Gram-negative research, such as Cubist’s acquisition of Calixa Therapeutics in 2009, and Novartis offering $485 million for rights to Paratek’s PTK0796, a promising broad-spectrum antibiotic in late stage clinical development.
Also of note, Tetraphase Pharmaceuticals, a small firm founded on synthetic chemist Andrew Myers’ academic research, develops new fully synthetic tetracyclines with improved substitution patterns. Tetracyclines, natural products originally isolated from soil samples in the 1940s, have shown good broad-spectrum antibacterial effects against both Gram-negative and Gram-postitive bacteria. The company announced last year that TP-434, their leading antibiotic candidate, had moved into Phase II. Maybe it can be ready for the next E. coli outbreak.
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