A team of scientists just won a battle in the war against antibiotic-resistant “superbugs” — and only time will tell whether their feat is akin to a bacterial Battle of Gettysburg that turns the tide toward victory.They won this particular battle, or at least gained some critical intelligence, not by designing a new antibiotic, but by interfering with the metabolism of the bacterial “bugs” — E. coli in this case — and rendering them weaker in the face of existing antibiotics, as reported today in Nature Biotechnology.It’s the “kick ’em when they’re down” style of fighting, and the team from Harvard’s Wyss Institute for Biologically Inspired Engineering and Boston University used sophisticated computer modeling and biotechnology as their weapons of choice.“We are in critical need for novel strategies to boost our antibiotic arsenal,” said senior author and Wyss core faculty member Jim Collins, a pioneer of synthetic biology who is also the William F. Warren Distinguished Professor at Boston University, where he leads the Center for BioDynamics. “With precious few new antibiotics in the pipeline, we are finding new ways to harness and exploit certain aspects of bacterial physiology.”In this case, the team targeted a little-understood but key part of bacterial metabolism called ROS production.ROS, or “reactive oxygen species,” include molecules like superoxide and hydrogen peroxide that are natural byproducts of normal metabolic activity. Bacteria usually cope just fine with them, but too many can cause serious damage or even kill the cell. In fact, Collins’ team revealed a few years ago the true antibiotic modus operandi: they kill bacteria in part by ramping up ROS production.The precise genetic mechanisms by which E. coli produces ROS remain elusive, Collins said, so his team adopted a standard computer model that maps out the way scientists currently understand E. coli metabolism. Collins’ team began by adding to this “system-level” metabolic model hundreds of reactions that are known to increase ROS production. Then they deleted various genes to see which were involved in ROS production, honed in on the suspected targets after running thousands of computer simulations, and validated the model in the laboratory — achieving 80 to 90 percent agreement with the model-based predictions.“The next challenge was to determine if increasing the ROS production by the cell itself would render it more susceptible to death by oxidative, ergo, antibiotic attack,” Collins said — and it did. The team deleted a series of genes that led to increased ROS production in the cell, they added different antibiotics and biocides such as bleach — known cell-killers by way of increasing ROS production — and the cells died at a much higher rate than the cells without the deleted genes. In short, by interfering with the bacterial metabolism, the antibiotics and biocides were even more lethal to the cells.“There is no magic bullet for the global health crisis we’re experiencing in terms of antibiotic-resistant bacteria,” said Don Ingber, Wyss founding director, “and yet there is tremendous hope in the kinds of pioneering systems biology approaches Jim and his team are spearheading.”The team’s next steps are to use molecular screening technologies to precisely identify molecules that boost ROS production, Collins said, and to test the approach used in this E. coli study on other kinds of bacteria — such as the mycobacteria responsible for tuberculosis, a potentially lethal lung disease.This work was funded by the Wyss Institute for Biologically Inspired Engineering at Harvard University, the National Institutes of Health Director’s Pioneer Award Program, and the Howard Hughes Medical Institute.
TraditionI’m a firm believer in tradition, particularly during the Holidays. For several years, I lived on the other side of the country, 2,000 miles away from my family. My Thanksgiving/Christmas tradition consisted of going for a long trail run in the morning, then eat a giant shrimp ring and drink martinis until the day faded to black.Traditions are important. But it’s also important that they evolve. We started a new Thanksgiving tradition this week that involved a massive family kickball tournament, unofficially sponsored by Yazoo Hefeweizen. My kids are 5—the perfect age to start developing wicked kickball skills. Their tiny little legs can’t get the ball over the bushes for a homerun, but they have a true passion for the sport. And talking trash, which is an often overlooked aspect of kickball.As for the beer—it was an out of left field choice at the beer store, but I’m convinced it was the perfect beer to get us through 12 hours of heavy eating and bloody kickball. Most people tend to opt for dark, malty beers during the Holidays (think imperial stouts, pumpkin porters and such), but you can only knock back one, maybe two of those rich beers before they start competing with the turkey and stuffing for space in your belly. And have you ever tried to steal third after downing an imperial bourbon stout?The Yazoo Hefe, on the other hand, is light and effervescent. It’s 5% ABV, tangy and a little bit fruity. It’s a marathon beer. You can pitch a full game of kickball with a bottle of this in your hand and still roll strikes. Then you can take that beer inside and sip it throughout a gravy-laden feast without missing a step. This, ladies and gentlemen, is a true Holiday Beer.Here’s to new traditions.And to the breweries out there, our family kickball team is currently looking for a title sponsor.