By screening bacterial genomes at scale, scientists are redefining the search for treatments against deadly infections like neonatal sepsis.
Klebsiella pneumoniae bacteria. Credit: Systems Chemical Biology of Infection and Resistance Laboratory.
A bacterium called Klebsiella pneumoniae most commonly causes pneumonia, but the resulting infection has an even more dangerous outcome in newborn babies.
“K. pneumoniae is the leading cause of severe neonatal sepsis, or blood poisoning, particularly in low- and middle-income countries,” says chemical biologist Eachan Johnson. “There are two major strains, one that spreads quickly in the community and one that’s becoming very resistant to drugs in hospitals. And there are now worrying reports of these two manifestations appearing at the same time.”
At the Crick, Eachan leads a lab working at the interface of genetics and chemistry, aiming to develop new strategies to fight back against bacteria that have evolved strong resistance to antibiotics like K. pneumoniae.
“Since penicillin was developed in the 1940s, there have been hardly any new antibiotics that work in different ways. They’ve all been marginal improvements on the same mechanism,” says Eachan. “Drugs that work in new ways are well overdue.”
Eachan believes we need to develop medicines from scratch that work differently, especially for drug-resistant infections like neonatal sepsis. His lab is joining an international challenge led by the Gates Foundation, Wellcome and the Novo Nordisk Foundation focusing on new antibiotics for Gram-negative bacteria, one of the leading drivers of drug resistance-related deaths.
“Gram-negative bacteria have a tough cell wall, which protects them against antibiotics,” explains Eachan. “They’re responsible for a whole host of diseases, from sepsis and meningitis to food poisoning, so we’re facing a ticking time bomb if we don’t find new ways to tackle them.”
Eachan’s three-year project will involve an innovative approach to find new ways to tackle K. pneumoniae. He’s building chemical libraries of around 100,000 potential molecules that could target fundamental bacterial proteins. He’ll then use computational methods to get these down to 100-200 based on the most promising molecules.
A petri dish growing K. pneumoniae for genetic screening to develop new antibiotics. Credit: Systems Chemical Biology of Infection and Resistance Laboratory.
“We’ll know these molecules are active against the bacteria, but not how they work,” he explains. “So, we plan to use CRISPR gene editing to edit out genes in the bacteria one by one, making hundreds of mutant strains. We’ll then treat them with the potential drug candidates and see which strains are most affected.”
This genetic approach will allow Eachan and his team to find molecules that work by a different mechanism of action. If certain genetically-edited strains are killed by the potential drugs, he’ll know that that gene is clearly important for the survival of the bacteria.
The idea is to develop a database of bacterial genes that help K. pneumoniae reproduce and spread, but, critically, could be targeted by drugs. Eachan will then share his findings with other teams in the programme, who will test these targets in animal models to see whether switching off the genes helps the host control the infection.
“Antibiotic resistance is such a huge challenge, I don’t think it would be possible to find solutions using just one approach,” Eachan concludes. “From geneticists to chemists, and the pharmaceutical industry, we all need to come together to pool our skills and data to make headway against diseases like sepsis that are becoming more and more drug-resistant.”
This Gates Foundation grant is part of the Gr-ADI initiative, a partnership between Wellcome, Novo Nordisk Foundation, and the Gates Foundation.
