TB research reveals new angle for drug research

Flasks for growing M. tuberculosis in the lab – the one of the left has low sodium chloride and is sensitive to antibacterials, where the one on the right has higher salt and the bacteria is resistant (still able to grow) in the presence of these drugs.©  Luiz Pedro Carvalho

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.