Understanding antibiotic-tolerant bacterial cells

Researchers from the MRC Centre for Molecular Bacteriology and Infection at Imperial College London have made an advance in understanding how a subset of bacterial cells escape being killed by many antibiotics. The study was supported by an Imperial College London Junior Research Fellowship, the Wellcome Trust and the Medical Research Council.

Writing in the journal Science, the researchers explained: “Bacterial persisters are antibiotic-tolerant cells, but little is known about their growth status and the signals and pathways leading to their formation in infected tissues.” The cells become persisters by entering a state in which they stop replicating and are able to tolerate antibiotics. This tolerant phase is only temporary but may contribute to the later development of resistance.

The team said they “used fluorescent single-cell analysis to identify Salmonella persisters during infection”. They showed that Salmonella forms large numbers of non-replicating persisters after being engulfed by immune cells called macrophages and being induced by vacuolar acidification and nutritional deprivation.

Animation showing a bacterial cell coming out of its persister state. As it divides, a preformed pool of green fluorescent protein is diluted out but new bacterial cells continue to make red fluorescent protein.

By adopting this non-replicating mode, Salmonella survives antibiotic treatment and lingers in the host, accounting for its ability to cause recurrent infections. The researchers also identified factors produced by human cells that trigger bacteria to become persisters.

One of the lead authors, centre director Professor David Holden, said: “One of the most striking findings in this work is that conditions inside immune cells activate two different responses from Salmonella, causing some bacteria to replicate and others to enter a non-replicating persister state. Activating these two responses together is likely to be an important mechanism by which Salmonella survives during infection.”

The other lead author, Dr Sophie Helaine, said, “Now we know the molecular pathways and mechanisms that lead to persister formation during infection, we can work on screening for new drugs to coax them out of this state so that they become vulnerable to antibiotics.”

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