Answer to bacterial mystery promises new antibiotics
role in building membranes of disease-causing bacteria has ended a
25-year mystery and paves the way for new drug development against
certain types of bacteria.
The researchers believe they have identified the first biochemical step that many disease-causing bacteria use to build their membranes. The finding is significant, as the biochemical step the antibiotic would block is not used by humans. Therefore, such a drug would not cause dangerous side effects.
The team have discovered that the disease causing pathogens use two enzymes, PlsX and PlsY, to kick off phospholipid synthesis.
"The biochemical pathway that uses PlsX and PlsY is the most widely distributed bacterial pathway for initiating the production of phospholipids," said the study's first author, Ying-Jie Lu of the St. Jude Department of Infectious Diseases.
This discovery has solved a mystery that has puzzled researchers for 25 years. Until now scientists have used E. coli bacteria as a model to understand how disease-causing bacteria make membrane phospholipids, but E. coli is an unsuitable model for most pathogens.
E. coli is a gram-negative bacterium, while many pathogens are gram-positive. Among these gram-positive organisms is Staphylococcus aureus, which causes skin infections and serious blood infections, and Streptococcus pneumoniae, which causes pneumonia.
Thus the scientists found that E. coli fused a molecule called G3P with a fatty acid in a single step. Rock's team showed that gram-positive pathogens first use PlsX to synthesize a compound called fatty acyl-phosphate, then use PlsY to transfer the fatty acid to G3P.
These steps initiate membrane phospholipid formation required for cell growth.
"Our discovery of PlsX and PlsY not only solved a troublesome mystery," said Charles Rock, a member of the St. Jude Department of Infectious Diseases and senior author of the paper.
"It's also important because identifying the essential components required for disease-causing bacteria to grow and multiply is a key part of developing new strategies for controlling infections."
As bacteria grow in size or divide, they must make additional membrane using a series of biochemical reactions. The first step in this process is the transfer of a fatty acid to a molecule called G3P.
Bacteria then convert this molecule into a variety of other molecules called phospholipids, which are the building blocks of membranes.
"We identified a biochemical process that uses a previously unrecognised molecule as a raw material to make phospholipid," Rock said.
Laboratory strains of E. coli do not cause disease; and the enzyme E. coli uses during the first step in making membranes does not exist in most other bacteria, including gram-positive pathogens.
Therefore, the way gram-positive bacteria make phospholipid building blocks has remained a mystery for over more than two decades.
