Scientists 'see' basis of drug resistance
resistance to common pathogenic bacteria, which could herald the
design and development of a new class of antibiotic drugs.
Bacteria that have become increasingly resistant to antibiotics has been an ongoing worldwide health problem that has threatened time and time again to spiral out of control, potentially creating a situation in which humans are virtually defenceless against the most simplest of bacterial infections.
Although the macrolide antibiotics such as erythromycin and azithromycin in this group are structurally different, their mechanism of action works by inhibiting the protein synthesis of bacteria, but not of humans. They bind tightly to an RNA site on the bacterial ribosomes, the cellular machinery that makes protein, but not to the human ribosomes.
Scientists from Yale University's molecular biophysics and biochemistry and chemistry department studied one of the ways in which bacteria can become resistant to macrolide antibiotics.
The researchers found that clinically important bacteria are resistant because of mutation of a single nucleotide base, from an A (adenine) to a G (guanine), in the site where macrolide antibiotics bind to the ribosome. The Yale group was able to "see" structural alterations when antibiotics were bound to ribosomes with different sensitivity to the drugs because of mutation.
This explains why the mutation has this effect. The mutant G has an amino group that pokes into the centre of the macrolide ring, causing it to back off the ribosome by an Angstrom or so.
"A major health concern of antibiotic resistance is that two million people every year get infections in hospital facilities and 90,000 per year die from them," said lead co-researcher, Professor Thomas Steitz.
"Macrolide-resistant Staphylococcus aureus is the most common of these infections."
The researchers discovered the change of that one base in the ribosomal RNA reduced the ability of the antibiotic to bind by a factor of 10,000.
Mutation of this type happens naturally, but rarely, only one in 100,000 to one in 10,000,000 bacterial mutations will cause this kind of resistance. However, each bacterium can divide as often as every 20 minutes, allowing one with a resistant mutation to rapidly cause a dangerous infection.
According to Centres for Disease Control and Prevention (CDC), nearly two million patients in the United States get an infection in the hospital each year. Of those patients, about 90,000 die each year as a result of their infection-up from 13,300 patient deaths in 1992.
More than 70 per cent of the bacteria that cause hospital-acquired infections are resistant to at least one of the drugs most commonly used to treat them. Persons infected with drug-resistant organisms are more likely to have longer hospital stays and require treatment with second or third choice drugs that may be less effective, more toxic, and more expensive
The recent advancements in the development of a new class of breakthrough antibiotics raise a glimmer of hope. The last time the industry targeted a new pathway with an antibiotic was the fluoroquinolone class in the 1960's. Fluoroquinolones now represent over $7 billion (€5.4 billion) in world wide annual sales.
Indeed, the annual cost for treating antibiotic resistant infections is approximately $30 billion (€25.7bn) in the USA alone.
