Francis Crick Institute-led research shows that sodium chloride
triggers phenotypic - or non-genetic - resistance to antibacterial
drugs by the bacteria that causes tuberculosis (TB) in humans.
The finding is important because it could lead to a new drug
target for TB - which can be difficult to treat and has high levels
of drug resistance - and it changes the way researchers might look
for better drugs in the future.
Dr Luiz Pedro Carvalho said: "While resistance to antibiotics by
bacteria such as Mycobacterium tuberculosis usually involves
genetic changes, sometimes resistance is observed even when there
are no genetic changes. This is known as phenotypic resistance.
"Phenotypic resistance usually affects several drugs that work
differently and have different chemical make-ups. The causes and
underlying mechanisms are not well understood. However in some
types of bacteria scientists have shown that changes in the
chemical reactions that keep the bacteria alive, as well as slow
growth rate, can cause phenotypic resistance."
The team carried out live imaging of cells infected with the TB
bacteria. By doing this they found that during infection, M.
tuberculosis is exposed to higher and more variable concentrations
of sodium chloride than that used in the media used in a lab to
grow bacteria. Common antibiotics are significantly weaker in the
presence of higher sodium chloride concentrations. The experiments
were carried out in a range of TB strains that are all known to
cause human disease.
In contrast to previous results, the researchers identified a
number of changes in the composition of the TB cell envelope - the
outer layer of the cell - which explained the
sodium-chloride-induced phenotypic resistance to antibacterial
drugs. The findings could explain why some drugs used to treat the
diseases are not very effective.
Dr Carvalho said: "This work has three important implications.
First, the cell envelope response to physiologic levels of sodium
chloride might represent a new target for antibacterial drug
discovery. Drugs that block this pathway might increase the
effectiveness of currently used antibacterial agents such as
aminoglycosides and quinolones.
"Second, the work suggests that to improve our changes of
finding new superior drugs, we should be looking for compounds that
are equally active at high and low sodium chloride
concentrations.
"Third, the work illustrates once again how the host environment
alters, and in this case decreases, the sensitivity of the TB
bacteria to antimicrobial agents. Our results clearly demonstrate
that some antimicrobials such as ethionamide, ethambutol,
aminoglycosides and quinolones might be less effective against the
TB bacteria due to the previously unappreciated levels of sodium
chloride in macrophages."
The paper, Cell-envelope
remodelling as a determinant of phenotypic antibiotic tolerance in
Mycobacterium tuberculosis, is published in ACS Infectious
Diseases.