Solution to Bacterial Mystery Promises New Drugs

A 25-year quest to identify the first biochemical step that many disease-causing bacteria use to build their membranes has led to a discovery that holds promise for effective, new antibiotics against these bacteria, according to investigators at St. Jude Children's Research Hospital. The finding is significant because the biochemical step the antibiotic would block is not used by humans. Therefore, such a drug would not cause dangerous side effects.

A report on this finding appears in the September 1 issue of Molecular Cell. The discovery also demonstrated that current textbooks use the wrong type of bacterium as a model to explain a critical biochemical step that most disease-causing bacteria use to make their membranes, according to Charles Rock, Ph.D., a member of the St. Jude Department of Infectious Diseases and senior author of the paper. 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 unrecognized molecule as a raw material to make phospholipid,” Rock said. “That discovery solved a mystery that has puzzled researchers for 25 years.”

Scientists have used E. coli bacteria for many years as a model to understand how disease-causing bacteria make membrane phospholipids, but E. coli is an unsuitable model for most pathogens (disease-causing bacteria), according to Rock.

First, E. coli is a so-called gram-negative bacterium, while many of the pathogens researchers are interested in are gram-positive, Rock noted. Among those gram-positive organisms are Staphylococcus aureus, which causes skin infections and serious blood infections, and Streptococcus pneumoniae, which causes pneumonia. The terms “gram-positive” and “gram-negative” refer to the response of bacteria to a standard laboratory process by which they are stained as a first step in identification.

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 remained a mystery for over more than two decades. Now, however, the St. Jude team reports that the gram-positive pathogens use two enzymes, called PlsX and PlsY, to kick off phospholipid synthesis.

“In fact, the biochemical pathway that uses PlsX and PlsY is the most widely distributed bacterial pathway for initiating the production of phospholipids,” explained the study’s first author, Ying-Jie Lu, Ph.D., of the St. Jude Department of Infectious Diseases. “It turns out that E. coli is more of an oddball rather than in the mainstream when it comes to how it makes membranes.”

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E. coli fuses 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,” Rock said. “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.”

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