The study detecting an selective membrane targeting repurposing antibiotic with activity against persistent methicillin-resistant Staphylococcus aureus; and fighting drug-resistant bacteria some of the scariest, most dangerous bugs on the planet. verify how bithionol a drug used to treat parasitic infections can weaken the cell membranes of persister cells of methicillin-resistant Staphylococcus aureus (MRSA), a deadly staph bacterium.
They also synthesized new compounds, to learn more about how bithionol works and enhance its potential for clinical use. The lab hums with activity, even during the summer months. Afternoon light spills through the glass walls, reflecting off beakers and the plastic safety glasses of students working amid the rows of lab benches.
Selective membrane targeting
Antibiotic resistant infections lead to 23,000 deaths a year in the United States and the problem is growing worldwide. By 2050, the World Health Organization projects that superbugs will become the number one killer globally, surpassing cancer. The goal of all of our projects is to help people,” Wuest says. The PNAS paper is the latest in a series of Emory collaborations on “persister” cells of MRSA with senior author Eleftherios Mylonakis, an infectious disease specialist at Rhode Island Hospital and Brown University.
The multi-disciplinary consortium also includes Harvard and Northwestern universities. ersisters are like enemy “sleeper” cells, Wuest explains. Antibiotics are looking for something that’s actively growing to attack. MRSA persisters are a subtype of cells that shut down and go dormant so the antibiotics can’t find them. The consortium ran hi-throughput analyses of thousands of drug candidates to see if any inhibited MRSA persister growth.
Two step synthesis
After they got a hit for bithionol, which is used to treat worm infections, they ran computer simulations showing that the compound interacted differently with MRSA cells compared to human cells. The result is a simple compound that is inexpensive and easy to make in a two-step synthesis. Mouse studies by the consortium showed that when bithionol is used with the antibiotic gentamicin, the combination clears persistent MRSA infections.
Post-doctoral fellows in the Wuest lab, like Taylor Hari, mentor students when they first join the group; training them to later take the lead on such challenging projects and become mentors themselves. The selectivity of bithionol results from the presence of cholesterol in mammalian but not in bacterial membranes. We also show that the antipersister potency of membrane-active antimicrobial agents correlates with their ability to increase membrane fluidity. Many people may not know how critical the need is to find new ways to combat antibiotic infections