School of Medicine’s biochemistry department team, in partnership with Q2 Pharma, to develop antivirulence agents that disarm bacteria of deadly toxins
Case Western Reserve University and Q2 Pharma Ltd., an Israeli biopharmaceutical company, have signed a two-year option to license small molecule, antivirulence technology with the potential to treat bacterial infections such as methicillin-resistant staphylococcus aureus (MRSA). Use of these novel agents in patients could revolutionize the treatment of bacterial infections.
“Superbugs” are bacteria that have developed resistance to antibiotics for which current antibiotics are no longer effective. Ever-increasing antibiotic resistance endangers patients as doctors run out of treatment options.
The Centers for Disease Control and Prevention (CDC) report that more than two million people develop antibiotic-resistant infections in the U.S. every year, leading to 23,000 deaths. Some experts say that without new inroads, the death toll could top that from cancer or heart disease by 2050. The financial costs are already enormous: as much as $20 billion in extra health care spending annually.
“Superbugs threaten to undo many of the enormous health advances brought about by the development of antibiotics since penicillin was discovered by Alexander Fleming in 1928,” said Menachem Shoham, associate professor of biochemistry at CWRU School of Medicine, the scientist at the heart of the new effort. “Our work represents a game changer to address this mounting problem.”
Shoham and his research team have discovered and patented non-antibiotic antivirulence compounds that prevent disease-causing toxins from forming in gram-positive bacteria such as MRSA. Since the antivirulent compounds don’t jeopardize the survival of the bacteria, resistance isn’t likely to occur, and has not been observed to date.
One of the Shoham team’s small-molecule compounds, named F19, was effective in healing a MRSA skin infection in mice, and in combination with an otherwise ineffective antibiotic, also reduced bacterial presence in the wounds. F19 has also demonstrated effectiveness against other gram positive “Superbugs,” including the deadly Clostridium difficile (C. diff.), Bacillus anthracis (the causative agent of anthrax), Staphylococcus epidermidis typically infecting catheters and implants, Streptococcus pyogenes (the causative agent of strep throat) and Streptococcus pneumoniae, one of the causes of acquired pneumonia and meningitis.
F19 works by binding to a protein involved in expressing disease-causing toxins, thus preventing the bacteria from producing the toxins. Without the toxins, the bacteria are benign. F19 also blocks the formation of biofilms—the slimy shells that bacteria encase themselves with for protection and which antibacterial drugs can’t penetrate.
“By killing bacterial pathogens, antibiotics eventually induce the organism to develop resistance,” said Shoham. “This is the case with once-highly-effective antibiotics such as penicillin. In contrast, our antivirulence agents strip the bacteria pathogen of its ability to produce harmful toxins without killing the pathogen. This results in little, if any, need to develop resistance. Without the toxins, the bacteria remain harmless, so people can go about their lives without any sign of disease.”
While bacterial infections could be cured by anti-virulence agents such as F19 without the need for antibiotics, in severe cases or for immunocompromised patients, combination therapy with a low-dose antibiotic may be appropriate. “The potential drugs we developed have the additional benefit of enabling the use of ‘old’ antibiotics in combination therapy,” said Shoham.
The two-year option to license agreement, managed through Case Western Reserve’s Technology Transfer Office, will enable human testing of the Shoham-team’s antivirulence agents and potential use by patients.
“We have been supporting the intellectual property around this innovative technology since its inception through patents and by assisting with various funding opportunities,” said Stephanie Weidenbecher, Technology Transfer Office licensing manager. “We are excited to have found a partner in Q2 Pharma to further develop the technology.”
Other Case Western Reserve faculty members participating in the research are Mahmoud Ghannoum (dermatology); Rajesh Viswanathan (chemistry); Clifford Harding (pathology). William Harte, a chief translational officer at the medical school, also provided assistance.
Initial pilot funds for this research were provided by the School of Medicine’s Council to Advance Human Health. Further research and development funds have been provided by The Dr. Ralph and Marian Falk Medical Research Trust, as a Catalyst Award and a Transformational Award, totaling $1.4 million.