Scientists have made an important advance in understanding how a
subset of bacterial cells escape being killed by many
antibiotics.
The cells become 'persisters' by entering a state in which they
stop replicating and are able to tolerate antibiotics. Unlike
antibiotic resistance, which arises because of genetic mutations
and is passed on to later generations, this tolerant phase is only
temporary, but it may contribute to the later development of
resistance.
Researchers from the Medical Research Council Centre for
Molecular Bacteriology and Infection (MRC CMBI) at Imperial College
London have succeeded in visualising persister cells in infected
tissues for the first time, and have identified signals that lead
to their formation.
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Virtually all bacterial species form subpopulations of
persisters that are tolerant to many antibiotics. Persisters are
likely to be a cause of many recurrent infections, but little is
known about how they arise.
The team developed a method for tracking single cells using a
fluorescent protein produced by the bacteria. They showed that
Salmonella, which causes gastroenteritis and typhoid fever, forms
large numbers of non-replicating persisters after being engulfed by
immune cells called macrophages. 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, Dr Sophie Helaine of the MRC CMBI at
Imperial, said: "We rely on antibiotics to defend us against common
bacterial infections like tuberculosis, cystitis, tonsillitis and
typhoid, but a few cells can escape treatment by becoming
persisters, which allows the infection to come back. This is a big
problem in itself, but it also makes it more likely that antibiotic
resistance will arise and spread.
"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."
The other lead author, Professor David Holden, Director of the
MRC CMBI, 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 paper, Internalization
of Salmonella by Macrophages Induces Formation of Nonreplicating
Persisters, is published in Science.