A new approach to outwit resistance to antibiotics has been discovered by a team of researchers who hope to apply this knowledge to form new strategies and targets to combat drug-resistant bacteria ubiquitous in both hospital settings and the larger community.
The discovery represents hope for the pharmaceutical industry, which face reductions in the useful lifespan of antibacterial products, the increasing cuts to R&D budgets and the rise in hospital infections such as vancomycin-resistant enterococci (VRE) and methicillin-resistant Staphylococcus aureus (MRSA)
Such is the threat of drug resistant bacteria, a curb on usage has been deemed ineffective and has prompted official regulators to place greater demands on manufacturers. For example, recent approval of Aventis' ketolide antibiotic Ketek (telithromycin) was held up by the US Food and Drug Administration for several months by requests for additional data on resistant strains.
The researchers' approach was to use a natural process called plasmid incompatibility. The theory was that if there is one plasmid in a cell and another one is introduced, then they compete with each other for resources.
The technique mimicked plasmid incompatibility by incubating bacteria containing plasmids with a specific compound, in this case an aminoglycoside called apramycin that binds to plasmid-encoded RNA and prevents proper plasmid reproduction.
Positively charged apramycin bound to negatively charged plasmid-encoded RNA, which allowed apramycin to prevent the actions of the protein that triggers plasmid reproduction. By thwarting that protein, apramycin blocked plasmid replication.
Lead researcher, Paul Hergenrother, led his team from The University of Illinois to experiment with the apramycin treatment, which was applied to bacterial cultures that were grown for 250 generations. By the end of the experiment, the plasmids no longer were present, making it possible for antibiotics to work.
"This is the first demonstration of a mechanistic-based approach to systematically eliminate the plasmids," Hergenrother said. "Standard antibiotics target the cell wall, but as resistance to antibiotics emerges, there needs to be other targets. We validated that plasmids as a new target for antibiotics."
Hergenrother said that further studies were needed to identify whether apramycin was useful against the plasmids occurring in different strains of antibiotic-resistant bacteria. It is possible that other compounds may be needed to target specific plasmids.
According to the National Institute of Health in the US, antibiotic resistance has led to more deaths from infection, longer hospital stays and a greater use of more toxic and expensive drugs.
The phenomenon is not restricted to North America as reports from the UK National Audit Office state that at any one time, 9 per cent of NHS hospital patients are suffering from an infection such as MRSA, acquired whilst in surgery or as an inpatient on the hospital wards. These 'nosocomial' infections affect 100,000 people annually, costing the National Health Service £1 billion (€1.5bn), and causing up to 5,000 deaths.