Antibiotic resistant bacteria are spreading, and the number of drugs that work against them is shrinking. University of Connecticut researchers searching for new antibiotics that can beat penicillin-resistant bugs were awarded more than $1.5 million on Jan. 22 by a consortium including the Novo Nordisk Foundation, Wellcome, and the Gates Foundation.
Penicillin changed the world when it was introduced during World War II, making once life-threatening infections easily treatable. It works by binding to an enzyme that helps protein in the outer membrane of bacteria cross-link to other proteins. Without the cross-links strengthening their outer shell, bacteria easily burst open and die.
But bacteria soon developed resistance. By the 1960s, penicillin-resistant organisms were commonly found in Europe, the UK, and the US. New antibiotics were developed, but new resistance followed. Last year the World Health Organization reported that one in six bacterial infections worldwide is antibiotic resistant.
Resistance has spread even as the supply of new antibiotics has come to a near standstill. New medicines are needed. To help, the Novo Nordisk Foundation, Wellcome, and the Gates Foundation are jointly launching the Gram-Negative Antibiotic Discovery Innovator (GrADI) to support early drug discovery for gram negative bacteria such as those that cause salmonella, meningitis, various kinds of pneumonia, gonorrhea, and many other diseases. GrADI gives grants to researchers looking for new antibiotics with broad spectrum activity against that family of bacteria. Klebsiella, a genus of bacteria that cause pneumonia, will be the common test organism for the researchers.
The UConn School of Medicine team of Rebecca Page, Wolfgang Peti, and Meng Choy have been awarded more than $1.5 million to pursue a project that looks for better ways to stop bacteria from cross-linking the protein-glycan molecules in their outer membrane. They have studied those proteins—called penicillin-binding proteins, because penicillin was discovered first—for more than 10 years. And they have a strategy for a new antibiotic. Instead of interfering directly with the cross-linking, they envision a drug that prevents the penicillin-binding proteins from allowing the protein-glycan molecules from getting close enough to even try to link up.
“It also means if the bacteria mutates to stop interacting with that antibiotic, it will also eliminate its ability interact with the protein-glycan molecules, preventing the cross linking,” says Page. “That is, the strategy will have high barriers to the development of antibiotic resistance, as any mutation that prevents antibiotic binding will also compromise its cross-linking function, making the bacteria unable to survive.”
The UConn team will focus on finding small molecules that bind to the key spot on the protein they are targeting, and then examining them with Nuclear Magnetic Resonance spectroscopy and X-ray crystallography to detect interactions and binding. Once they find small molecules that bind well to promising spots on the protein, they will try to make them larger by adding more chemical groups. Their ultimate goal is to have several drug candidates that bind tightly and specifically to the right spot on the protein.
A fundamental part of the GrADI initiative is data sharing, and the UConn team will enter a data-sharing consortium as part of the project. Twice a year, all the teams will come together to discuss their findings and progress against Klebsiella. The data sharing was part of the appeal of the grant. The researchers look forward to interacting with microbiologists and synthetic chemists who can help them find the right mechanisms and build good drug candidates.
They also look forward to “working with Novo Nordisk to take these into testing, and eventually into the clinic,” as new, safe, and effective antibiotics, Page says.
