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GEN News Highlights : Nov 12, 2013
Monkey Wrenching S. pneumoniae with Zinc
Zinc has long been known to have antibacterial properties, but only recently have scientists discovered how it actually works. In a study of Streptococcus pneumoniae, scientists have found that zinc appears to “jam shut” a protein transporter in the bacteria, preventing the uptake of manganese. Without manganese, S. pneumoniae cannot invade and cause disease in humans.
The details of S. pneumoniae’s vulnerability were uncovered by scientists based at the University of Adelaide and the University of Queensland. They published their results November 10 in Nature Chemical Biology, in a paper entitled “Imperfect coordination chemistry facilitates metal ion release in the Psa permease.”
The study reveals that the bacterial transporter, known as PsaBCA, uses a spring-hammer mechanism to bind divalent metals such as manganese and zinc. The difference in size between these two metals causes the transporter to bind them in different ways. In the case of zinc, the smaller of the two metals, transporter binding goes awry. The spring-hammer mechanism closes too tightly around the zinc, causing an essential spring in the protein to unwind too far, jamming it shut and blocking the transporter from being able to take up manganese.
“Without manganese, these bacteria can easily be cleared by the immune system,” said Christopher McDevitt, Ph.D., project leader and research fellow at the University of Adelaide. “For the first time, we understand how these types of transporters function. With this new information we can start to design the next generation of antibacterial agents to target and block these essential transporters.”
In their paper, Dr. McDevitt and colleagues describe how they combined high-resolution structural data, metal-binding assays, and mutational analyses to show that the inability of the transporter protein to satisfy the preferred coordination chemistry of manganese enables the protein to undergo the conformational changes required for cargo release to the Psa permease. According to the authors, the conformational changes occur with manganese ions, not zinc ions, which remain bound to transporter protein.
The techniques used by the researchers allowed them to show “at an atomic level of detail how this transport protein is responsible for keeping the bacteria alive by scavenging one essential metal (manganese), but at the same time also makes the bacteria vulnerable to being killed by another metal (zinc),” said Bostjan Kobe, Ph.D., a professor of structural biology at the University of Queensland. In fact, say the authors, by blocking an essential pathway, zinc causes the bacteria to starve.
By revealing how deadly bacteria may be starved, Dr. McDevitt’s group has demonstrated the value of their research, which focuses on the role of membrane proteins in bacterial pathogenesis. An explanation of this focus posted on Dr. McDevitt’s website notes that while membrane proteins account for about one-third of the proteins encoded by the genome, the challenges in their isolation and handling have meant that they have remained relatively poorly characterized compared to their soluble counterparts.
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