Menachem Shoham, PhD, associate professor and researcher in the department of biochemistry at the Case Western Reserve University School of Medicine in Cleveland, has identified new anti-pathogenic drugs that, without killing the bacteria, render methicillin-resistant Staphylococcus aureus (MRSA) harmless by preventing the production of toxins that cause disease.
MRSA is the most prevalent bacterial pathogen in hospital settings and in the community at large. The problem has become increasingly severe due to the fact that the bacteria develop resistance to antibiotics. Currently, there are only two antibiotics available to treat MRSA (vancomycin and linezolid) and strains are emerging that are resistant even to these two remaining antibiotics. As result, healthcare providers are running out of options to treat patients suffering from antibiotic-resistant infections, creating a dire need for alternative treatments and approaches.
"Staph bacteria are ubiquitous and normally do not cause infections, however, occasionally these bacteria become harmful due to their secretion of toxins," says Shoham. "We have discovered potential 'anti-pathogenic' drugs that block the production of toxins, thus rendering the bacteria harmless. Contrary to antibiotics, these new anti-pathogenic drugs do not kill the bacteria. And since the survival of the bacteria is not threatened by this approach, the development of resistance, like that to antibiotics, is not anticipated to be a serious problem."
Shoham identified a bacterial protein, known as AgrA, as the key molecule responsible for the release of toxins. AgrA, however, needs to be activated to induce toxin production. His goal was to block the activation of AgrA with a drug, thus preventing the cascade of toxin release into the blood that can lead to serious infections throughout the body. The screening for AgrA inhibitors was initially carried out in a computer by docking a library of 90,000 compounds and finding out which compounds would fit best into the activation site on AgrA. Subsequently, about 100 of the best scoring compounds were acquired and tested in the laboratory for inhibition of the production of a toxin that ruptures red blood cells. Seven of these compounds were found to be active. Testing compounds bearing chemical similarity to the original compounds led to the discovery of additional and more potent compounds. More than a dozen active compounds have been discovered by this method. The best drug candidate reduces red blood cell rupture to 12 percent of the value without the drug at a concentration of 10 µg/mL, without affecting bacterial growth..
"It is possible to inhibit virulence of MRSA without killing the bacteria," Shoham says. "Such anti-pathogenic drugs may be used for prophylaxis or therapy by themselves or in combination with an antibiotic."
Funding was provided by grants from STERIS Corporation and from the American Heart Association. The results were presented at the 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) earlier this week.