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Los Alamos scientists are taking an in-depth look at how bacteria defeat death-by-antibiotics. SOME BACTERIA ARE ESPECIALLY TOUGH. For billions of years, bacteria have evolved numerous mechanisms to protect themselves from toxic chemicals in their environment—some of which we humans now use as antibiotics. Applying their time-tested methods of thwarting chemical threats, these hardy microbes are responsible for nearly two million antibiotic- resistant infections annually in the United States. Bacteria have developed many types of defenses. Like layering for winter, some microbes wear complex coatings to serve as physical barriers to the outside world. In addition, bacteria can literally stick together to create an even stronger barrier and communication network, through which they share their defense strategies. Bacteria have even developed mechanisms to spit out any foreign toxins that get through the barriers. But if those toxins are antibiotics, intended to protect a patient against the targeted bacteria, then the patient’s ability to conquer the infection might be compromised. This spitting-out system is made possible by a set of proteins that work together as a molecular machine to pump the antibiotics out of the bacterium. These so-called efflux pumps are the most widespread and important mechanisms in multidrug antibiotic resistance. However, a complete and quantitative picture of efflux-mediated resistance is lacking. And this is a problem because bacteria are becoming resistant to more and more of the available antibiotics, putting humanity on the brink of a public-health crisis. A multidisciplinary team of Los Alamos scientists is working on a project to understand how efflux pumps work. The researchers’ goal is simple: to deactivate the bacteria’s efflux pumps, thereby preventing the world’s supply of antibiotics from becoming defunct. [ To learn more about the problem of antibiotic resistance, see “The Mold Rush” in the October 2015 issue of 1663]. Gnana Gnanakaran, a theoretical biologist at Los Alamos, is the lead for the project targeting bacterial efflux pumps. Gnanakaran has gathered together a world-class collection of scientists connected by the Laboratory but widely diverse in their expertise. The group includes nearly 20 researchers, divided into teams: mathematicians and computational modelers, molecular and cell biologists, and structural biologists. Their task is to dissect all aspects of efflux pumps— their construction, how they pump out noxious molecules, and how bacteria regulate their production and use. A family of efflux pumps called resistance-nodulation- division (RND) is the target of the team’s research. The focus is on RND pumps from two types of gram-negative bacteria, Pseudomonas aeruginosa and Burkholderia pseudomallei. Gram-negative bacteria have two membranes, with a space between the membranes called the periplasm. These bacteria Bacterial efflux pumps are molecular mechanisms for removing toxins—including antibiotics. Learning to thwart their operation by understanding how the pumps work, how they are regulated, and their role in bacterial communities is key to defeating a major type of antibiotic resistance.