Scientists at Harvard Medical School and Brigham and Women's Hospital have identified two families of proteins that allow bacteria to grow, multiply, and infect, solving what researchers call one of the few remaining mysteries in an intensely studied area of biology.
- By JAKE MILLER
The findings, reported in two studies in Nature, could open the doors to a new generation of wide-spectrum antibiotics - those capable of killing multiple types of bacteria.
Scientists have long known that a specific transporter molecule ferries raw materials from the interior of cells to walls outside to build a variety of structures essential for bacterial life. But the identity of another key player in this process remained a mystery: the molecules that coax the transporters to flip back inside the cell and pick up more cargo to continue their work.
Working independently, two research teams - both affiliated with HMS' Department of Microbiology - have now unmasked the identity of two families of proteins that trigger the transporter molecules to somersault back to the inside of the cell. These transport catalysts, known as flippases, function across a wide swath of bacteria, including those that cause some of the world's deadliest diseases, such as cholera.
David Rudner, professor of microbiology in the Blavatnik Institute at HMS, and colleague Ian Roney made their discovery using Bacillus subtilis, a soil bacterium widely used in biological research and in the biotech industry.
Matt Waldor, HMS Edward H. Kass Professor of Medicine at Brigham and Women's Hospital, and colleagues studied Vibrio cholerae, the bacterium that causes cholera.
Both identified the protein families UptA and PopT as the flippases that recycle the transporter molecule UndP, which carries molecules made in the cytoplasm of the cell to the cell surface, where they take part in many cellular processes critical for bacterial growth and survival.
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Biologists have been trying to identify the various tools and materials that bacteria use to build and remodel their cell wall for processes like growth, reproduction, and spore formation because this knowledge can shed light on two critical questions: How do these materials and tools enable bacteria to infect their hosts? How can these processes be interrupted to weaken and kill bacteria?
Rudner and Roney successfully showed that UptA and PopT flippases from various bacterial pathogens are capable of recycling UndP in B. subtilis, showing that these families of flippases function to recycle UndP in a wide variety of bacteria. UndP recycling is the crucial final step in virtually all the processes that build and remodel the outer surface of the cell.
"This discovery completes the parts list for the processes that diverse bacteria rely on to grow and to reproduce and represents a new set of targets for future antibiotics," Rudner said.
Given that the same type of molecules are used as flippases across such a wide swath of different bacteria suggests that targeting these specific molecules could empower a new class of antibiotics that would be useful against many different pathogens, the researchers said.
New insight into cholera infection and bacterial physiology
Waldor and co-authors found that the same two families of transporter proteins were required for synthesis of the bacterial cell wall in V. cholerae and demonstrated that the bacteria need at least one of these transporters to cause successful infection in an animal model of cholera-like disease. They also discovered that each UndP flippase family functioned best in different environmental conditions, suggesting that microbes can use these proteins to support cell growth across a wide range of habitats.
"This discovery is a major advance in microbial cell biology and adds an important layer to our understanding of how bacteria, including pathogens, adapt to ever-shifting environments," Waldor said.
Authorship, funding, disclosures
The Rudner study was supported by the National Institutes of Health (GM086466, GM127399, GM145299 and U19 AI158028).
For the Waldor study, additional authors included Brandon Sit, Veerasak Srisuknimit, Franz Zingl and Karthik Hullahalli of HMS and Emilio Bueno and Felipe Cava of Umeå University in Sweden.
The study was supported by the National Institutes of Health (R01AI-042347 and F31AI156949), Howard Hughes Medical Institute, National Sciences and Engineering Research Council of Canada (PGSD3-487259-2016), Swedish Research Council, Knut och Alice Wallenbergs Stiftelse, Laboratory of Molecular Infection Medicine Sweden, and Kempe Foundation.
This story includes material adapted from a Brigham and Women's news release.
