Digging Up New Antibiotics
Posted on by Dr. Francis Collins
Last fall, President Obama issued an Executive Order aimed at combating a growing public health threat: antibiotic-resistant infections that claim the lives of 23,000 Americans every year . So, I’m pleased to report that biomedical research has made some exciting progress on this front with the discovery of what promises to be a powerful new class of antibiotic drugs—the first such discovery in more than 25 years.
There are two significant things about this feat. The first is that the new antibiotic, called teixobactin, not only has the ability to kill a wide range of infection-causing bacteria, but to kill them in a way that may greatly reduce the problem of resistance. The second is that researchers identified teixobactin using an ingenious approach that enhances our ability to search one of nature’s richest sources of potential antibiotics: soil [2, 3].
That’s right, plain old dirt—in this case, soil from a grassy field in Maine—yielded the biological lead that enabled a team led by NIH-supported researchers at Boston’s Northeastern University to develop teixobactin. Sound bizarre? In fact, many of the antibiotic drugs prescribed today were originally derived from the natural toxins that soil-dwelling bacteria and fungi use to kill their microbial competitors. However, over the past few decades, scouring the soil for new antibiotics has proven to be extremely difficult because the vast majority of dirt-dwelling microbes can’t be grown under traditional microbiological conditions in the laboratory.
In a study published in the journal Nature, Northeastern’s Kim Lewis and Slava Epstein describe the innovative approach they used to cultivate these elusive bugs in laboratory conditions. They began by taking 1 gram of soil, mixing it with a little water and some nutrient-rich broth, and pipetting the resulting “soup” onto an iChip—a miniature device capable of trapping a single microbe in each of its many wells. Once microbes were trapped, the permeable device was placed into a bucket of soil, where it was allowed to incubate for 1 month. Under these conditions, many of the microbes replicated and formed thriving colonies, which could then be removed from the iChip and cultivated on Petri dishes in the lab.
In collaboration with colleagues from Germany, England, and NovoBiotic Pharmaceuticals (Cambridge, MA), Lewis’s team used the iChip approach to study 10,000 different species of soil bacteria. All told, the researchers isolated more than 25 potential new drug compounds, including a number of possible antibiotics, an anti-cancer agent, and a compound that specifically targets the bacteria that causes tuberculosis.
However, the most exciting discovery was teixobactin, a defensive toxin made up of just a few amino acids in an unusual arrangement, produced by the newly identified proteobacteria species Eleftheria terrae. The enthusiasm centers on the ability of this particular toxin to kill bacteria through a mechanism quite different from existing antibiotics.
Specifically, teixobactin binds to a pyrophosphate-sugar site in key components of the outer walls of many bacteria. When such binding occurs, the bacterial walls fall apart—an action highlighted in the drug’s name, which incorporates the Greek word for wall: teixos. And because this mechanism of action doesn’t involve proteins, researchers think bacteria will be far less likely to develop resistance to teixobactin than to the many current antibiotics that target proteins, which often evolve to produce resistance.
Test-tube experiments showed that teixobactin had excellent activity against 19 types of gram-positive bacteria, including the widely feared methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VREs) that are now immune to most other antibiotics. Furthermore, when teixobactin was given to mice, researchers found that it was well tolerated and highly effective in combating both MRSA and Streptococcus pneumoniae infections.
Still, much work remains to be done before we can even begin to think of using teixobactin in the clinic. More safety and efficacy testing is needed in animal models to lay the groundwork for possible human clinical trials, perhaps within a couple of years. Also, it’s important to note that teixobactin is not active against gram-negative bacteria, which include the deadly and rapidly emerging threat of Klebsiella and other carbapenem-resistant Enterobacteriaceae (CREs).
As encouraging as the discovery of a possible new class of antibiotics may be, the latest advance is just one part of NIH’s ongoing battle against antibiotic-resistant infections. Besides research aimed at finding new antibiotics, we are supporting efforts to: enhance clinical trial networks to test new ways of treating and preventing such infections; develop rapid, point-of-care diagnostics to identify highly resistant bacterial infection (including a major prize); and create a new generation of vaccines aimed at MRSA and other drug-resistant microbes.
 Antibiotic/Antimicrobial Resistance Threat Report 2013, Centers for Disease Control and Prevention.
 A new antibiotic kills pathogens without detectable resistance. Ling LL, Schneider T, Peoples AJ, Spoering AL, Engels I, Conlon BP, Mueller A, Schäberle TF, Hughes DE, Epstein S, Jones M, Lazarides L, Steadman VA, Cohen DR, Felix CR, Fetterman KA, Millett WP, Nitti AG, Zullo AM, Chen C, Lewis K. Nature. 2015 Jan 7.
 Antibiotics: An irresistible newcomer. Wright G. Nature. 2015 Jan 7.
The Lewis Lab, Northeastern University, Boston
Sample America, non-profit effort to discover infectious disease cures through classroom experiments
Report to the President on Combating Antibiotic Resistance, President’s Council of Advisors on Science and Technology
The perpetual challenge of antimicrobial resistance. Fauci AS, Marston HD. JAMA. 2014 May 14;311(18):1853-4.
Video: The Perpetual Challenge of Antimicrobial Resistance: Will We Lose the Race or Change the Game? Dr. Anthony S. Fauci, NIH 2014 Demystifying Medicine Series, 2014 January 7.
NIH support: National Institute of Allergy and Infectious Diseases, NIH Common Fund
Tags: antibiotic-resistant infections, antibiotics, drug discovery, Eleftheria terrae, gram-negative bacteria, gram-positive bacteria, iChip, Maine, new antibiotic drugs, pyrophosphate, soil, teixobactin