Genentech researchers have found a chink in the armor of drug-resistant, gram-negative bacteria called the BamA enzyme, which is found in the bugs' outer membrane. And they've found a way to attack this protein with an antibody—an approach that they say could pave the way for a new class of antibiotics to plug a treatment gap.
Antibiotic-resistant bugs are on the rise, but gram-negative bacteria are a particularly tricky foe. Instead of having a single cell membrane, like most organisms, they have two. Each membrane has distinct properties, so getting a molecule through both of them is a tall order, said Steven Rutherford, a scientist at Genentech and corresponding author of the study, in an interview with FierceBiotechResearch.
Rutherford's team targeted BamA, an enzyme that builds the outer membrane of gram-negative bacteria by folding and inserting proteins into it. They chose BamA because it is present in all gram-negative bacteria, involved in a fundamental cell process, and exposed on the cell surface, eliminating the need to penetrate the cell.
The team used a monoclonal antibody to block BamA function in E. coli, a gram-negative bacterium that has demonstrated drug resistance. This compromised the outer membrane, killing the bacteria. The findings appear in Proceedings of the National Academy of Sciences.
While their initial goal was to identify a therapeutic antibody, there are some limitations on moving it forward as a treatment, Rutherford said. In order to get at the BamA to see if their approach would work, the team had to contend with lipopolysaccharide (LPS) in the outer membrane. Because it is difficult to get antibodies through this thick sugar layer, they removed it for the study, Rutherford said.
Even if Genentech doesn’t ultimately develop an antibody-based antibiotic for gram-negative bacteria, the research opens a number of doors for superbug-targeting treatments, Rutherford said. “We used that antibody to ask some biological questions and learn about how Bam works,” he said. “It gives us an understanding of what it would take to inhibit this. It allows us to develop plans for the future to target this BamA machinery, because it does present as a really useful and viable drug target.”
The race is on to find alternatives to currently available antibiotics. The CDC estimates that 23,000 Americans with superbug infections die each year. And these bugs are increasing the burden on health systems—a Health Affairs study found that antibiotic resistance added $1,383 to the cost of treating a patient with a bacterial infection.
Genentech's work won’t stop at BamA. “We can apply methods to find other antibodies that target other cell processes in the hope that we might find that rare superstar antibody,” Rutherford said.