HONG KONG – A University of Hong Kong (HKU) study has shown that a new small-molecule non-antibiotic compound has potent efficacy against methicillin-resistant Staphylococcus aureus (MRSA), making it a promising lead compound for developing anti-virulence drugs against S. aureus.
This would be the first such antivirulence agent to become available, since "presently, there are no non-antibiotic antivirulence compounds available on the market and in use clinically," said study leader Richard Kao, an associate professor in the Department of Microbiology of the Li Ka Shing Faculty of Medicine at HKU.
Multidrug resistant (MDR) bacteria such as MRSA are a rapidly increasingly prevalent problem worldwide. In 2007 the World Health Organization, for example, cautioned that "we are running out of antibiotics, and the discovery of new antibiotics is far slower than bacteria rising resistance."
"We will soon revert to the pre-antibiotic era when MDR is so widespread that most bacterial pathogens are 'immune' to antibiotics, so new treatments that do not give rise to antibiotic resistance are urgently needed," Kao told BioWorld Asia.
Using a chemical genetics approach, the researchers screened a library containing more than 50,000 small-molecule compounds for antivirulence activity against S. aureus.
Small molecules have two advantages for drug development, noted Kao. "Small molecular structures are easier to optimize, in order to increase potency and other desirable properties, while generally being more readily absorbed and distributed in the body to gain to access the infection sites."
Kao and his team identified the antivirulence properties of the small-molecule compound M21, which was shown to inhibit the expression of multiple virulence factors in S. aureus via inhibition of the bacterial protease enzyme ClpP, which is a major virulence regulator.
In particular, "M21 was shown to alter alpha-toxin expression in a ClpP-dependent manner, which indicates that a good inhibitor of ClpP can shut down the production of several virulence factors, including the major virulence factor alpha-toxin," explained Kao.
"This also illustrates that ClpP is indeed the molecular target of M21, as when ClpP gene was deleted from MRSA, M21 showed no repressive effect on alpha-toxin production," he added.
The study further demonstrated that in a mouse model of bacteremia in which the animals were infected with S. aureus, those treated with M21 had significantly fewer bacteria and abscesses in their kidneys and greater survival than untreated mice.
"While the untreated vehicle group showed a survival rate of 40 percent, while the M21 treatment infected group showed 100 percent protection," said Kao. "Histologically, no staphylococcal abscess communities (SACs) were found in treated mice, while numerous SACs were seen in the vehicle group."
These findings strongly suggest that M21 may prove to be a potential alternative to antibiotics for the treatment of increasingly problematic MRSA infections.
"We have identified a new non-antibiotic lead compound for the development of future antivirulence-based drugs, which may lead to the development of a new generation of drugs that prevent and control bacterial infections without eliciting antibiotic resistance," Kao concluded.
"We are currently trying to optimize the structure of this promising lead compound, M21, in order to find a drug candidate with the potential to proceed towards clinical trials."