The last antibiotics produced against Gram-negative bacteria – which tend to be more dangerous – were developed in the 1960s. Thanks to the increasing resistance to antibiotics, we need more. But instead of bothering to do our own, scientists have been looking for other species that may have to kill the same bacteria we do ̵
The latest organisms that researchers have searched for are bacteria in the microbiomes of roundworms that parasitize insects (called nematodes technically enteropathogenic). They were considered promising candidates as the worms invade insect larvae and release bacteria. These bacteria must then defend those already living in the insect larva as well as all other bacteria that have just spit out the nematodes. Fittingly, these species contain common pathogens in our own intestines, such as E. coli .
When microorganisms are tested for their effectiveness as antibiotics, they are usually cultured on a plate together with the pathogenic bacteria to determine if the bacteria tested hinder the growth of the target bacteria. The species taken from the intestine of the nematodes have not stopped the growth of E. coli in this traditional assay. But the scientists speculated that they might still make antibiotics, but not enough.
And they were right. Concentrated extracts of nematode intestinal cultures ceased E. coli from the growth.
The active ingredient in the extracts was a seven amino acid peptide chain, a shorter version of a protein. The peptide chain is not normally formed when the bacteria are grown under laboratory conditions, and is formed in other contexts only slowly and in small quantities. The explorers called it darobactin. It is produced by a number of different bacterial species, including Yersinia pestis the Gram-negative bacterium that causes the plague.
Darobactin is too large to pass through the outer membrane of the Gram-negative bacterium. To find out how it worked, the researchers generated a mutant E. coli resistant to it by breeding m in its presence. The generation of resistance lasted a whole week. The resistant strains all had mutations in a protein called BamA, which encodes a chaperone protein. The job of this chaperone is to put proteins contained in the outer membrane of the bacteria in the right place and help them to fold into the correct three-dimensional orientations.
Darobactin binds to BamA after it has been attached to one of these outer membrane proteins, thereby fixing it in place and preventing the formation of a functional outer membrane. BamA is one of only two essential proteins expressed on the outer surface of Gram-negative bacteria. If these nematodes form a molecule that targets it, we can exploit it, perhaps other microorganisms as well.
Nature 2019. DOI: 10.1038 / s41586-019-1791-1 (About DOIs).