Public health has a looming, if slow-simmering, crisis. Antibiotics, which revolutionized health care in the 20th century, are losing their punch. Evolution, it turns out, is pretty effective at producing things that don’t die. Accordingly, bacteria are evolving resistance to our antibiotic arsenal, and more people are suffering from previously-treatable infections.
Meanwhile, the pipeline of new antibiotics has been clogging. Among the blockages are high drug-development costs, low economic incentives, and the fact that it’s just plain hard to make drugs that poison bacteria, don’t poison people, and can actually get inside the bugs. Historically, the “golden era” of antibiotic discovery came from mining biodiversity. Bacteria are constantly poisoning each other in microbial warfare, so raiding their armory of pre-designed chemical weapons turned out to be a good strategy. Unfortunately, we dug up all the easily mined antibiotics fairly quickly, and synthetic drugs, even using new genomics data, haven’t been very effective.
Uncovering New Antibiotics from Microbial Dark Matter
Recently, there’s been a call to go back into the biodiversity mines, this time looking for microbial “dark matter” – the ~99% of bugs that we know are there because of high-throughput sequencing, but that cannot be cultured in the lab. Heeding the call, a team from Boston and Germany pulled out their shovels and started sifting for antibiotic gold with their iChip, a specially-designed platform for culturing the unculturable.
The iChip has a central plate with a grid of tiny holes that are filled with soft nutrient agar. Before the agar is loaded, a soil sample is suspended in it, diluted so each hole gets only one bacteria or archaea. Then the chip is sealed on both sides with semi-permeable membranes, and put back into the soil. The cells are effectively back in their natural habitat with all its nutrients and neighbors, and they form nice, isolated colonies for the miners to study when they dig up the chip a month later.
One of the uncultured bacteria rendered cultured by the iChip was Eleftheria terrae, which was particularly good at killing Gram-positive bacteria, even the infamously drug-resistant MRSA. In fact, the antibiotic it made, dubbed teixobactin, was almost too good. Even when the team tried all of the worst-case scenarios for promoting drug resistance, they couldn’t evolve a resistant strain. Normally, that means they have a nonspecific poison that will kill eukaryotes (like us) too, but when they dumped a batch of teixobactin on some mammalian cells and held their breath, the cells lived.
Teixobactin – the First in a New Line of Antibiotics?
With further study, it turned out teixobactin blocks peptidoglycan synthesis by binding to highly-conserved lipids in bacterial cell walls, which explains why it doesn’t hurt mammalian cells (no cell walls) or Gram-negative bacteria (protected by an outer membrane). This also makes teixobactin similar to vancomycin, one of the closest things we have to bacterial kryptonite. Vancomycin is a last line of defense against drug-resistant Gram-positives, and it saw no resistance for 30 years. Even when vancomycin-resistant strains did develop, it looks like they didn’t evolve resistance genes on their own – they stole them from the species that makes vancomycin itself (and needs them as antidote).
Teixobactin, the miners hope, will be even more vanquishing than vancomycin. For one thing, they speculate, the E. terrae that makes it probably doesn’t have resistance genes for other bugs to steal, so teixobactin may remain irresistible even longer. Unlike the vancomycin-producer, E. terrae is Gram-negative, so it is protected simply by its outer membrane. Second, teixobactin is better at actually killing Gram-positives, even when they’re not growing. This may be because it releases bacterial autolysins – cell wall enzymes that, like jackhammers on a highway, are necessary for growth, but can create ill-placed holes when not properly controlled.
Teixobactin has already been used to cure mice of bacterial infections in the lab, and it may soon find its way to a pharmacy near you. That would be a more-than-welcome drip from the antibiotic pipeline, and it could be the first in a new era of drug discovery, aided by clever techniques, like the iChip, to culture the uncultured and illuminate dark biodiversity.
Mine your own insights from the original paper: Nature, January 2015.