Molecular drills can target and destroy deadly bacteria that have resistance to nearly all antibiotics

A Klebsiella pneumoniae bacteria exposed to motorized nanomachines invented at Rice and the antibiotic meropenem shows signs of damage in a transmission electron microscope image. The yellow arrows show areas of cell wall disruptions, while the purple arrow shows where cytoplasm has escaped from the cell. Image by Don Galbadage/Texas A&M

Rice, Texas A&M-led research shows motors kill bacteria, revive some antibacterial drugs

Molecular drills have gained the ability to target and destroy deadly bacteria that have evolved resistance to nearly all antibiotics. In some cases, the drills make the antibiotics effective once again.

Researchers at Rice University, Texas A&M University, Biola University and Durham (U.K.) University showed that motorized molecules developed in the Rice lab of chemist James Tour are effective at killing antibiotic-resistant microbes within minutes.

“These superbugs could kill 10 million people a year by 2050, way overtaking cancer,” Tour said. “These are nightmare bacteria; they don’t respond to anything.”

The motors target the bacteria and, once activated with light, burrow through their exteriors.

While bacteria can evolve to resist antibiotics by locking the antibiotics out, the bacteria have no defense against molecular drills. Antibiotics able to get through openings made by the drills are once again lethal to the bacteria.

The researchers reported their results in the American Chemical Society journal ACS Nano.

Tour and Robert Pal, a Royal Society University Research Fellow at Durham and co-author of the new paper, introduced the molecular drills for boring through cells in 2017. The drills are paddlelike molecules that can be prompted to spin at 3 million rotations per second when activated with light.

Tests by the Texas A&M lab of lead scientist Jeffrey Cirillo and former Rice researcher Richard Gunasekera, now at Biola, effectively killed Klebsiella pneumoniae within minutes. Microscopic images of targeted bacteria showed where motors had drilled through cell walls.

“Bacteria don’t just have a lipid bilayer,” Tour said. “They have two bilayers and proteins with sugars that interlink them, so things don’t normally get through these very robust cell walls. That’s why these bacteria are so hard to kill. But they have no way to defend against a machine like these molecular drills, since this is a mechanical action and not a chemical effect.”

The motors also increased the susceptibility of K. pneumonia to meropenem, an antibacterial drug to which the bacteria had developed resistance. “Sometimes, when the bacteria figures out a drug, it doesn’t let it in,” Tour said. “Other times, bacteria defeat the drug by letting it in and deactivating it.”

He said meropenem is an example of the former. “Now we can get it through the cell wall,” Tour said. “This can breathe new life into ineffective antibiotics by using them in combination with the molecular drills.”

Gunasekera said bacterial colonies targeted with a small concentration of nanomachines alone killed up to 17% of cells, but that increased to 65% with the addition of meropenem. After further balancing motors and the antibiotic, the researchers were able to kill 94% of the pneumonia-causing pathogen.

Tour said the nanomachines may see their most immediate impact in treating skin, wound, catheter or implant infections caused by bacteria — like staphylococcus aureus MRSAklebsiella or pseudomonas — and intestinal infections. “On the skin, in the lungs or in the GI tract, wherever we can introduce a light source, we can attack these bacteria,” he said. “Or one could have the blood flow through a light-containing external box and then back into the body to kill blood-borne bacteria.”

“We are very much interested in treating wound and implant infections initially,” Cirillo said. “But we have ways to deliver these wavelengths of light to lung infections that cause numerous mortalities from pneumonia, cystic fibrosis and tuberculosis, so we will also be developing respiratory infection treatments.”

Gunasekera noted bladder-borne bacteria that cause urinary tract infections may also be targeted.

The paper is one of two published by the Tour lab this week that advance the ability of microscopic nanomachines to treat disease. In the other, which appears in ACS Applied Materials Interfaces, researchers at Rice and the University of Texas MD Anderson Cancer Center targeted and attacked lab samples of pancreatic cancer cells with machines that respond to visible rather than the previously used ultraviolet light. “This is another big advance, since visible light will not cause as much damage to the surrounding cells,” Tour said.

Learn more: Deadly ‘superbugs’ destroyed by molecular drills

 

 

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DNA origami joins forces with molecular motors to build nanoscale machines

Hundreds or even thousands of DNA propellers can fit on one microscopic slide

A new spin on DNA

Every year, robots get more and more life-like. Solar-powered bees fly on lithe wings, humanoids stick backflips, and teams of soccer bots strategize how to dribble, pass, and score. The more researchers discover about how living creatures move, the more machines can imitate them all the way down to their smallest molecules.

“We have these amazing machines already in our bodies, and they work so well,” said Pallav Kosuri. “We just don’t know exactly how they work.”

For decades, researchers have chased ways to study how biological machines power living things. Every mechanical movement—from contracting a muscle to replicating DNA—relies on molecular motors that take tiny, near-undetectable steps.

Trying to see them move is like trying to watch a soccer game taking place on the moon.

Now, in a recent study published in Nature, a team of researchers including Xiaowei Zhuang, the David B. Arnold Professor of Science at Harvard University and a Howard Hughes Medical Institute Investigator, and Zhuang Lab postdoctoral scholar Pallav Kosuri and Benjamin Altheimer, a Ph.D. student in the Graduate School of Arts and Sciences, captured the first recorded rotational steps of a molecular motor as it moved from one DNA base pair to another.

In collaboration with Peng Yin, a professor at the Wyss Institute and Harvard Medical School, and his graduate student Mingjie Dai, the team combined DNA origami with high-precision single-molecule tracking, creating a new technique called ORBIT—origami-rotor-based imaging and tracking—to look at molecular machines in motion.

In our bodies, some molecular motors march straight across muscle cells, causing them to contract. Others repair, replicate or transcribe DNA: These DNA-interacting motors can grab onto a double-stranded helix and climb from one base to the next, like walking up a spiral staircase.

To see these mini machines in motion, the team sought to take advantage of this twisting movement. First, they glued the DNA-interacting motor to a rigid support. Once pinned, the motor had to rotate the helix to get from one base to the next. So, if they could measure how the helix rotated, they could determine how the motor moved.

But there was still one problem: Every time one motor moves across one base pair, the rotation shifts the DNA by a fraction of a nanometer. That shift is too small to resolve with even the most advanced light microscopes.

Two pens lying in the shape of helicopter propellers gave the team an idea: A propeller fastened to the spinning DNA would move at the same speed as the helix and, therefore, the molecular motor. If they could build a DNA helicopter large enough that the swinging rotor blades could be visualized, they could capture the motor’s elusive movement on camera.

To build molecule-sized propellers, Kosuri, Altheimer and Zhuang decided to try DNA origami. Used to create artdeliver drugs to cellsstudy the immune system, and more, DNA origami involves manipulating strands to bind into beautiful, complicated shapes outside the traditional double-helix.

“If you have two complementary strands of DNA, they zip up,” Kosuri said. “That’s what they do.” But, if one strand is altered to complement a strand in a different helix, they can find each other and zip up instead, weaving new structures.

For help constructing their propellers, the team enlisted Peng Yin, a pioneer of DNA origami technology. With guidance from Yin and his graduate student Dai, the team wove almost 200 individual pieces of DNA snippets into a propeller-like shape 160 nanometers in length. Then, they attached the blades to a regular double-helix and fed the other end to RecBCD, a molecular motor that unzips DNA. When the motor got to work, it spun the DNA, twisting the propellers like a corkscrew.

“No one had seen this protein actually rotate the DNA because it moves super-fast,” Kosuri said.

The motor can move across hundreds of bases in less than a second. But, with their origami propellers and a high-speed camera running at a thousand frames per second, the team could finally record the motor’s fast rotational movements.

“So many critical processes in the body involve interactions between proteins and DNA,” said Altheimer. Understanding how these proteins work—or fail to work—could help answer fundamental biological questions about human health and disease.

So, the team started to explore other types of DNA motors. One, RNA polymerase, moves along DNA to read and transcribe the genetic code into RNA. Inspired by previous research, the team theorized this motor might rotate DNA in 35-degree steps, corresponding to the angle between two neighboring nucleotide bases.

ORBIT proved them right: “For the first time, we’ve been able to see the single base pair rotations that underlie DNA transcription,” Kosuri said. Those rotational steps are, as predicted, around 35 degrees.

Millions of self-assembling DNA propellers can fit into just one microscope slide, which means the team can study hundreds or even thousands of them at once, using just one camera attached to one microscope. That way, they can compare and contrast how individual motors perform their work.

“There are no two enzymes that are identical,” Kosuri said. “It’s like a zoo.”

One motor protein might leap ahead while another momentarily scrambles backwards. Yet another might pause on one base for longer than any other. The team doesn’t yet know exactly why they move like they do. Armed with ORBIT, they soon might.

ORBIT could also inspire new nanotechnology designs powered with biological energy sources like ATP. “What we’ve made is a hybrid nanomachine that uses both designed components and natural biological motors,” Kosuri said.

One day, such hybrid technology could be the literal foundation for biologically-inspired robots.

Learn and see more: A new spin on DNA

 

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Biological “dynamic networks” could inspire molecular machines, swarming robots

Fire ants form a raft during flooding. (Credit: CC photo by Turnbull FL via Wikimedia Commons)

Think of it as mathematics with a bite: Researchers at CU Boulder have uncovered the statistical rules that govern how gigantic colonies of fire ants form bridges, ladders and floating rafts.

The research, published last week in the Journal of the Royal Society Interface, takes a unique look at one of the strangest, and potentially painful, networks in nature. Fire ants (Solenopsis invicta) are resourceful builders, using their own bodies to create gigantic structures made up of hundreds to thousands of insects and more.

In the new study, a team led by CU Boulder’s Franck Vernerey set out to lay out the engineering principles that underlie these all-ant structures—specifically, how they become so flexible, changing their shapes and consistencies within seconds. The group used statistical mechanics to calculate the way that ant colonies respond to stresses from the outside, shifting how they hang onto their neighbors based on key thresholds.

The findings may also help researchers understand other “dynamic networks” in nature, including cells in the human body, said Vernerey, an associate professor in the Department of Mechanical Engineering.

Such networks “are why human bodies can self-heal,” Vernerey said. “They are why we can grow. All of this is because we are made from materials that are interacting and can change their shape over time.”

Ant armada

They can also float: Fire ant colonies gained some fame in 2017 when videos from the aftermath of Hurricane Harvey in Texas showed these insects riding out the flood waters by banding together into rafts.

Such structures may be an insectophobe’s nightmare, but they’re an engineer’s dream. That’s because while individual ants have simple brains, their colonies display surprisingly intelligent behavior. That’s a trait that scientists would like to mimic as they develop new types of polymers and swarms of robots that can work together seamlessly.

Fire ants are “a bio-inspiration,” said Shankar Lalitha Sridhar, a graduate student in mechanical engineering at CU Boulder and a coauthor of the new study. The goal is “to mimic what they do by figuring out the rules.”

To begin to understand those rules, the team turned to experimental results collected by scientists at Georgia Tech University. Those researchers found that fire ant colonies maintain their flexibility through a fast-paced dance. To glom onto each other, individual ants hang onto the insects next to them using the sticky pads on their feet. But they also don’t stay still: In a typical colony, those ants may shift the position of their feet, grabbing onto a different neighbor every 0.7 seconds.

The team from CU Boulder wanted to find out how the ants govern this internal cha-cha in response to outside pressures. To do that, Vernerey and his colleagues used a mathematical tool that allowed them to average out the behavior of the hundreds to thousands of ants in a colony.

“When look at an aggregation, you don’t really care what one ant does,” said Tong Shen, a graduate student in mechanical engineering and a coauthor of the study. “You just look at the population.”

Tap dance

The researchers, who also included graduate student Robert Wagner, discovered that as the forces on ant colonies increase, the insects pick up their speed. If the force on an individual ant’s leg hits more than eight times its body weight, the insect will compensate by switching between its neighbors twice as fast.

“If you start to increase your rate of shear, then you will start stretching their legs a little bit,” Vernerey said. “Their reaction will be, ‘oh, we are being stretched here, so let’s exchange our turnover rate.’”

That behavior explains why ant colonies are classified as “shear-thinning” fluids, or materials that get thinner the more force you put on them—think stirring a can of paint.

But if you keep increasing the forces on the ants, they can no longer keep up. When that happens, the ants will stop letting go of their neighbors and instead hold on for dear life.

“Now, they will be so stressed that they will behave like a solid,” Vernerey said. “Then at some point you just break them.”

The researchers explained that they’ve only just scratched the surface of the mathematics of fire ant colonies. But their calculations are general enough that researchers can already begin using them to explore designs for new dynamic networks, including molecular machines that deliver drugs directly to cells.

 

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Light-controlled gearbox for nanomachines

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Rewarded with a Nobel Prize in Chemistry in 2016, nanomachines provide mechanical work on the smallest of scales. Yet at such small dimensions, molecular motors can complete this work in only one direction. Researchers from the CNRS’s Institut Charles Sadron, led by Nicolas Giuseppone, a professor at the Université de Strasbourg, working in collaboration with the Laboratoire de mathématiques d’Orsay (CNRS/Université Paris-Sud), have succeeded in developing more complex molecular machines that can work in one direction and its opposite. The system can even be controlled precisely, in the same way as a gearbox.

The study was published in Nature Nanotechnology on March 20, 2017.

Molecular motors can produce cyclical mechanical movement using an external energy source, such as a chemical or light source, combined with Brownian motion (disorganized and random movement of surrounding molecules). However, nanomotors are exposed to molecular collisions on all sides, which complicates the production of directed and hence useful mechanical work. The first molecular motors from the 2000s used the principle of the “Brownian ratchet,” which like a notch on a cogwheel that prevents a mechanism from moving backwards, will bias Brownian movement so that the motor functions in only one direction. This makes it possible to provide useable work, but it does not allow for a change in direction.

The research team thus set out to find a solution for reversing this movement, which they did by connecting motors to molecular modulators (clutch subunits) using polymer chains (transmission subunits). A mathematical model has also been established to understand the behavior of this network.

When exposed to ultraviolet irradiation, the motors turn while the modulators remain immobile. The polymer chains thus wind around themselves, and contract like a rubber band that shortens as it is twisted. The phenomenon can be observed on a macroscopic scale, as the molecules form a material that contracts.

When the molecules are exposed to visible light, the motors stop and the modulators are activated. The mechanical energy stored in the polymer chains then rotates the modulators in the opposite direction of the original movement, and the material extends.

More spectacular still, the researchers were able to demonstrate that the rate and speed of the work produced can be carefully regulated through a combination of UV and visible light, like a gearbox functioning through modulations in frequency between the motors and modulators. The team is now attempting to use this study to develop photomechanical devices that can provide mechanical work controlled by light.

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Molecular motors: Power much less than expected?

Feringa_chem_motor

“Our measurements are a bucket of cold water for designers of molecular nanomachines”

An innovative measurement method was used at the Institute of Physical Chemistry of the Polish Academy of Sciences in Warsaw for estimating power generated by motors of single molecule in size, comprising a few dozens of atoms only. The findings of the study are of crucial importance for construction of future nanometer machines – and they do not instil optimism.

Nanomachines are devices of the future. Composed of a very little number of atoms, they would be in the range of billionth parts of a meter in size. Construction of efficient nanomachines would lead most likely to another civilization revolution. That’s why researchers around the world look at various molecules trying to put them at mechanical work.

Researchers from the Institute of Physical Chemistry of the Polish Academy of Sciences (IPC PAS) in Warsaw were among the first to have measured the efficiencies of molecular machines composed of a few dozen of atoms. “Everything points to the belief that the power of motors composed of single, relatively small molecules is considerably less than expected”, says Dr Andrzej ?ywoci?ski from the IPC PAS, one of the co-authors of the paper published in the “Nanoscale” journal.

Molecular motors studied at the IPC PAS are molecules of smectic C*-type liquid crystals, composed of a few tens of atoms (each molecule is 2.8 nanometer long). After depositing on the surface of water, the molecules, under appropriate conditions, form spontaneously the thinnest layer possible – a monomolecular layer of specific structure and properties. Each liquid crystal molecule is composed of a chain with its hydrophilic terminal anchored on the surface of water. A relatively long, tilted hydrophobic part protrudes over the surface. So, monomolecular layer resembles a forest with trees growing at certain angle. The free terminal of each chain includes two crosswise arranged groups of atoms with different sizes, forming a two-blade propeller with blades of different lengths. When evaporating water molecules strike the “propellers”, the entire chain starts to rotate around its “anchor” due to asymmetry.

Specific properties of liquid crystals and the conditions of experiment give rise to an in-phase motion of adjacent molecules in the monolayer. It is estimated that “tracts of the forest” of up to one trillion (10^12) molecules, forming areas of millimeter sizes on the surface of water, are able to synchronise their rotations. “Moreover, the molecules we studied were rotating very slowly. One rotation could be as long as a few seconds up to a few minutes. This is a much desired property. Would the molecules be rotating with, for instance, megahertz frequencies, their energy could be hardly transferred on larger objects”, explains Dr ?ywoci?ski.

Earlier power estimations for molecular nanomotors were related either to much larger molecules, or to motors powered by chemical reactions. In addition, these estimations did not account for the resistance of the medium where the molecules worked.

Free, collective rotations of liquid crystal molecules on the surface of water can be easily observed and measured. Researchers from the IPC PAS checked how the speed of rotation changes as a function of temperature; they estimated also changes in (rotational) viscosity in the system under study. It turned out that the energy of single molecule motion generated during one rotation is very low: just 3.5·10^-28 joule. This value is as many as ten million times lower than the thermal motion energy.

“Our measurements are a bucket of cold water for designers of molecular nanomachines”, notices Prof. Robert Ho?yst (IPC PAS).

In spite of generating low power, rotating liquid crystal molecules can find practical applications. This is due to the fact that a large ensemble of collectively rotating molecules generates a correspondingly higher power. Moreover, a single square centimeter of the surface of water can accommodate many such ensembles with trillions of molecules each.

Read more . . .

 

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