Bacteria self-defense mechanisms uncovered, opening new drug targets
Evolution has obviously helped humans get to where we are today – but now it's working against us. Bacteria are rapidly developing resistance to our best drugs, hurtling us towards a future where antibiotics simply don't work anymore. Now a team of researchers has uncovered a potentially exploitable chink in the armor of a particularly troublesome group of bacteria.
Many antibiotics, including the original drug that started it all, penicillin, work by attacking the cell wall of bacteria. The problem is that a class of bugs called gram-negative bacteria have an extra outer membrane that protects them from these attacks. That makes them particularly hardy, and as such gram-negative bacteria are responsible for many of the most dangerous drug-resistant infections.
"Imagine a castle with an inner keep and an outer wall, with the outer wall or membrane protecting the bacteria from antibiotics," says Ian Henderson, an author of the study. "We're interested in how gram-negative bacteria build this outer membrane, because if we understand that, we can disable the membrane so antibiotics can get through and combat the infection."
Most pieces of the puzzle are already falling into place. It's known that outer membranes are made up of proteins, lipids and sugars, and it's understood how two of those pieces – the proteins and sugars – are produced inside the cell and how they're transported to the outer membrane. But the lipids remained elusive.
"We knew how these lipids were manufactured but not how they were transported through the cell to take their place in the outer membrane," says Henderson. "We have now discovered the cellular machinery responsible for exporting lipids to the outer membrane."
The team investigated the crystal structure of a protein called MlaC, and found a mechanism that seems to open and close a pocket that lipids bind to. That controls when the cellular machinery inside the cell can export the lipids to the outer membrane.
"Now that we understand how the lipid transport machinery functions, it opens up a new pathway for us to design medicines that can prevent the outer membrane from being fully constructed, allowing us to fight back against infectious bacteria," says Henderson.
The researchers have already managed to show just how this kind of knowledge could be put to work. In previous research, the team found that mutating the genes that drive lipid transport prevented the bacteria from becoming infectious.
The research was published in the journal Nature Microbiology.
Source: University of Queensland