In any battle, sizing up one's opponent is a critical first step. For researchers fighting a bacterial infection, that means assessing every nook and cranny of the malicious microorganism and identifying which ones to attack.
At the Center for Biological Research of the Spanish Research Council in Madrid, scientists are devising maneuvers they hope will take out bacteria at their molecular knees, and they are optimistic a recent advance will help yield therapies for a number of infections, including antibiotic-resistant strains delivering blow after blow in hospitals across the globe.
In a Journal of Biological Chemistry "Paper of the Week," Dr. Antonio J. Martín-Galiano and professor José M. Andreu are reporting that they have mapped out a promising target for a strategic hit after carefully analyzing a protein that bacteria need in order to reproduce and further infect hosts.
"Bacterial infections are a threat around the globe. This includes not only people in underdeveloped countries, but also patients compromised by the emergence of new antibiotic-resistant pathogens in First World communities and hospitals," Martín-Galiano said. "There is an urgent need to find new bacterial targets and new antibiotics with which to fight infections. Our work, by providing basic insight into the inner functional mechanisms of one new target, cell-division protein FtsZ, may be a little bit of help."
A bacterial cell reproduces through a process called binary fission. First, the parent cell's DNA duplicates so that the future daughter cell will have all the correct genetic information. Then, special building-block proteins, known as FtsZ, move inside the parent cell toward the center and get to work building scaffolding for the construction of a new dividing ring. FtsZ is believed to generate constriction force, while the cell wall keeps growing toward the center of the cell. Finally, the ring tightens like a noose and splits the cell in two, each with identical DNA.
Martín-Galiano and Andreu focused on how the FtsZ building blocks operate, hoping to understand better how their ever-changing shapes affect the creation of the cell-dividing wall. After all, if FtsZ could be manipulated, perhaps cell division, and replication of the bacteria, could be halted.
Scientists have understood for some time now that, during cell division, the FtsZ filaments assemble and disassemble repeatedly. When the filaments are in the assembly phase, they line up in a relatively straight fashion, and, when they are in the disassembly phase, they become somewhat curved.
But what has remained a mystery is what spurs the change between FtsZ's straight and curved states of being, and their team set out to answer the question: What makes FtsZ shape up just right for the job?
"That would be what is called the FtsZ switch, and it remained to be revealed," Andreu said.
That is, until now.
Andreu's team created computer models that predict the movements of the FtsZ molecules and from that data gleaned which pivot points and hinges allow them to change shape and assemble into straight and curved filaments. They then mutated a number of those moving parts, by switching up their constituent amino acids, and observed how the assembly-disassembly cycle was affected.
"This would be analogous to modifying gears of clockwork in a mechanical watch and then looking at the effects on its functioning," Andreu explained.
Some of the tweaks to the protein's amino acids didn't make much of a difference, and the FtsZ molecules went on with their business as normal: binding to each other, gobbling up energy molecules, breaking apart and repeating those steps about every 10 seconds. But other mutations made a world of difference and shelved FtsZ's cell-wall construction plans entirely.
"Several of the mutations blocked the transition of curved to straight FtsZ and produced spiral filaments instead of straight ones," Andreu said, and spiral filaments can't help the cell to divide. "Interestingly, these critical changes clustered around a cleft between two main moving parts of FtsZ, where a new antibacterial compound is thought to bind."
That compound, known as PC190723, was discovered by researchers at Prolysis Ltd. in 2008 in the United Kingdom and was shown to have antibacterial activity against several microbes, including the quite drug-resistant and virulent staph infection known as methicillin-resistant Staphylococcus aureus, or MRSA.
Now, with the new insights from Andreu's team, scientists are in a better position to pursue other compounds that might inhibit FtsZ's ability to build the bacterial cell wall by binding to the cleft between the two parts of FtsZ with greater specificity or efficiency – essentially mucking up FtsZ's gears.
The researchers performed their analysis and experiments on FtsZ from the archaebacterium Methanococcus jannaschii, which thrives in extreme environments, such as at hydrothermal vents on the seafloor.
"Given the large degree of structural similarity between most FtsZ proteins, including FtsZ from the pathogens that cause tuberculosis, pneumonia and other human infections, we hope that the results may be extrapolated to the FtsZ from pathogenic bacteria," Andreu said.
Andreu and Martín-Galiano's team also included Rubén M. Buey, a former group member who participated in the design of the project and analyzed the results, and Marta Cabezas, who purified many of the FtsZ protein variants.
The team's research was funded by the Spanish Ministry of Science, the Madrid Community and the Federation of European Biochemical Societies. The resulting "Paper of the Week" was published on the Journal of Biological Chemistry's website May 15 and will appear in the July 16 issue.
About the American Society for Biochemistry and Molecular Biology
The ASBMB is a nonprofit scientific and educational organization with more than 12,000 members worldwide. Most members teach and conduct research at colleges and universities. Others conduct research in various government laboratories, at nonprofit research institutions and in industry. The Society's student members attend undergraduate or graduate institutions. For more information about ASBMB, visit www.asbmb.org.
Angela Hopp | EurekAlert!
Closing in on advanced prostate cancer
13.12.2017 | Institute for Research in Biomedicine (IRB Barcelona)
Visualizing single molecules in whole cells with a new spin
13.12.2017 | Wyss Institute for Biologically Inspired Engineering at Harvard
MPQ scientists achieve long storage times for photonic quantum bits which break the lower bound for direct teleportation in a global quantum network.
Concerning the development of quantum memories for the realization of global quantum networks, scientists of the Quantum Dynamics Division led by Professor...
Researchers have developed a water cloaking concept based on electromagnetic forces that could eliminate an object's wake, greatly reducing its drag while...
Tiny pores at a cell's entryway act as miniature bouncers, letting in some electrically charged atoms--ions--but blocking others. Operating as exquisitely sensitive filters, these "ion channels" play a critical role in biological functions such as muscle contraction and the firing of brain cells.
To rapidly transport the right ions through the cell membrane, the tiny channels rely on a complex interplay between the ions and surrounding molecules,...
The miniaturization of the current technology of storage media is hindered by fundamental limits of quantum mechanics. A new approach consists in using so-called spin-crossover molecules as the smallest possible storage unit. Similar to normal hard drives, these special molecules can save information via their magnetic state. A research team from Kiel University has now managed to successfully place a new class of spin-crossover molecules onto a surface and to improve the molecule’s storage capacity. The storage density of conventional hard drives could therefore theoretically be increased by more than one hundred fold. The study has been published in the scientific journal Nano Letters.
Over the past few years, the building blocks of storage media have gotten ever smaller. But further miniaturization of the current technology is hindered by...
With innovative experiments, researchers at the Helmholtz-Zentrums Geesthacht and the Technical University Hamburg unravel why tiny metallic structures are extremely strong
Light-weight and simultaneously strong – porous metallic nanomaterials promise interesting applications as, for instance, for future aeroplanes with enhanced...
11.12.2017 | Event News
08.12.2017 | Event News
07.12.2017 | Event News
13.12.2017 | Health and Medicine
13.12.2017 | Physics and Astronomy
13.12.2017 | Life Sciences