In the search for new antibiotics to combat growing drug resistance, Gram-negative bacteria present a daunting challenge. These microbes sport a cell wall and a tight double membrane that create an often-insurmountable barrier for getting compounds into the cell.
A group based mostly at Genentech now reports a class of compounds called arylomycins that can sneak inside Gram-negative bacteria and kill some of the most resistant strains. What’s more, the research team, led by Christopher Heise of Genentech, thinks they’ve found a not-seen-before mechanism for one of the 1,000 or so arylomycin compounds they are testing (Nature 2018, DOI: 10.1038/s41586-018-0483-6).
The team synthesized derivatives of natural versions of arylomycins known to have some ability to get beyond the outer membrane of Gram-negative bacteria. Heise’s team tested these derivatives and found one compound called G0775 that is at least 500 times as potent as the natural precursors against cultured Gram-negative bacteria such as Escherichia coli and Klebsiella pneumoniae, and considerably active against Acinetobacter baumannii and Pseudomonas aeruginosa, which cause hospital-acquired infections. The compound also worked against drug resistant strains of those species, and in an animal model of infection.
Arylomycins generally work by gumming up the bacterial type I signal peptidase, an essential enzyme that chops a specific sequence of amino acids off of bacterial proteins, allowing the molecules to leave the inner area of the cell. Shutting down this enzyme makes it difficult for the cell to secrete myriad proteins, including housekeeping and virulence proteins, to its cell surface.
What is unusual about G0775 is how it gums up the peptidase. The enzyme has two key catalytic residues—a serine and a lysine. When attacking similar enzymes, drug molecules often target the serine. But the aminoacetonitrile warhead of G0775 instead forms a covalent amidine with the lysine.
“This functionality has never been seen,” Heise says. “It creates a very tight and irreversible bond.”
Other researchers in this field are jazzed about the findings—both the chemistry and the applicability.
“I think this is going to be a very serious shot on goal,” says Floyd Romesberg, who searchers for new antibiotics at Scripps Research Institute California. Serine-lysine enzymes are fairly rare in humans, he says, so the potential for off-target effects could be lower for G0775 or related compounds. He also says that the findings suggest chemists could consider targeting lysines, not just serines in drug design for similar enzymes.
Heise and other researchers in the field want to understand how these compounds get into Gram-negative bacteria. It doesn’t seem to be through the normal entry tunnels—proteins called porins, Heise says.
Paul Hergenrother, a chemist at the University of Illinois, Urbana-Champaign says arylomycins might not rely on molecules on the surfaces of bacteria, instead creating their own way through the outer membrane.
“The whole thing is interesting,” Hergenrother says. “The challenge for them is going to be to translate this.”
Heise says his group is continuing to optimize the arylomycins.