When it comes to antibiotic-resistant bacteria, so-called Gram-negative bugs are the most worrisome to scientists and drug developers. That’s because these bacteria have not one but two membranes that shield them against antibiotic attacks.
Scientists at Genentech have found a way to penetrate Gram-negative bacteria that they hope will lead to a whole new class of antibiotics. Working in partnership with RQx Pharmaceuticals, they’ve developed a molecule called G0775 and shown in both cell samples and mouse models that it works against several Gram-negative bacteria that have become resistant to nearly all marketed antibiotics. The research was published in the journal Nature.
Genentech’s scientists started with a class of naturally occurring molecules called arylomycins, which are active against Gram-negative bacteria. They work by inhibiting bacterial type I signal peptidase (SPase), an enzyme that resides between the cytoplasmic and outer membranes and that’s essential for the bugs’ survival. SPase sits on the surface of the second protective membrane, so it's easier to reach than other targets.
“The second membrane is basically the equivalent of a force field. It protects the cell from antibiotics penetrating into its cell interior,” said Chris Heise, Ph.D., a senior scientist for biochemical and cellular pharmacology and infectious diseases at Genentech, in a video produced by the company.
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Problem is, the natural forms of arylomycins are not potent enough. So Heise and his team created more than 1,700 analogs of the natural product in an effort to improve its ability to penetrate the outer membrane and target SPase. It worked against laboratory strains of Gram-negative bacteria.
“That was an aha moment for us, that we could kill these bugs,” said Peter Smith, Ph.D., a scientist in Genentech’s infectious diseases unit, in the video.
They then reached out to the Centers for Disease Control and Prevention (CDC). “It collated a collection of highly multidrug-resistant isolates,” Smith said, including severe Escherichia coli, that the researchers could use to further test the efficacy of the compounds.
They zeroed in on G0775, showing it could work against multidrug-resistant E. coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii, which collectively are known as ESKAPE pathogens. They confirmed the activity of G0775 in several mouse models of bacterial infections.
The study follows a discovery earlier this year by a separate Genentech team, which focused on an enzyme called BamA, found in the outer membranes of Gram-negative bacteria. They used a monoclonal antibody to inhibit BamA in drug-resistant E.coli. In that case, they removed a thick sugar layer from the bacterium’s outer membrane to get the antibody through it, but they believe the study provided key insights for the future development of antibodies that can penetrate and kill multidrug-resistant bugs.
Every year, more than 2 million Americans contract antibiotic-resistant infections, and 23,000 people die, the CDC estimates. There have been no new classes of antibiotics approved to treat Gram-negative infections in 50 years.
Genentech partnered with RQx Pharmaceuticals five years ago with the goal of developing drugs derived from naturally occurring compounds that can evade mechanisms bacteria use to build resistance. The companies have not yet provided a timeline for the further development of G0775.