Overprescription of antibiotics pressures bacteria to evolve resistance. The rise of antibiotic-resistant “superbugs” – harmful bacteria that cannot be treated with antibiotics – is an often overlooked threat to public health. The World Health Organization, however, recognizes bacterial antibiotic resistance as a “major threat,” and the problem is gaining media attention including a recent Science in the News article [1,2].

Recently, a research team from Northeastern University led by Kim Lewis discovered a new antibiotic in a soil sample from Maine []. Heralded by major press outlets as a “powerful” and “promising” discovery, a veritable “antibiotic pay dirt,” there are great expectations for this new antibiotic and its effectiveness against these superbugs [4,5,6]. Why is creating new antibiotics to treat superbugs such a challenge for scientists? How is this newly discovered antibiotic more effective at treating them? And most importantly, what can we realistically expect for the future of this drug?

Where do antibiotics come from?

Bacteria in the wild must fight to survive, competing against other microorganisms for space, nutrients, and other resources. Over time, they develop compounds that help kill off their bacterial competitors, facilitating their own survival. These compounds present a wealth of potential antibiotics we can use to fight infection. While bacteria are found almost everywhere in the world, one of the main sources for many of the early antibiotics was soil, which has a high microbial diversity. Soil bacteria, however, remain largely unstudied even today because only a small percentage of them can be grown in the laboratory where we can harvest and purify their antibiotic products.

Figure 1~ Bacteria producing a compound of interest are grown, or “cultured,” in a lab. By providing nutrients, oxygen, and a lot of space, scientists can produce a large quantity of these bacteria and thus a large quantity of the antibiotic. The antibiotic can be extracted from the bacteria and purified [].

To grow, or “culture,” bacteria in the lab normally, we place the bacteria in a nutrient-rich environment that contains a mixture of the chemicals necessary for growth. If you put a soil sample on a plate containing this growth medium, however, you would run into something known as “The Great Plate Count Anomaly”: 99% of the bacteria you can see in the soil sample under a microscope won’t grow on the plate []. This is one of the main obstacles to finding new antibiotics. Because only 1 out of 100 bacterial species will grow in the lab, we miss out on studying 99% of the potential sources of antibiotics.

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These bacteria have been nicknamed “dark matter bacteria” because they are reminiscent of dark matter in physics. They make up a large percentage of the bacteria in the world, but we know next to nothing about them. If we could find a way to study them, we would have many new avenues to explore in the search for antibiotics – and just such an attempt enabled the discovery of Lewis’s new antibiotic, teixobactin.

Culturing the Uncultured

While dark matter bacteria refuse to grow in a traditional laboratory setting, they do thrive in the soil. What if we could trick the lab bacteria into thinking they’re still growing in soil? Scientists are beginning to engineer soil-like environments where never before studied bacteria can be grown in the lab. While not widely used, this method has been successfully attempted in the past; several research groups managed to grow previously uncultured bacteria from various marine sediment samples using this technique [].

To use this technique, Lewis’s research group developed the iChip. The iChip consists of a metal plate with small holes, or wells, each of which is filled with a combination of a sample of bacteria and regular lab bacteria growth medium. This central plate is then surrounded by semi-permeable membranes on both sides and placed back into the soil.

Figure 3~ Set-up of the iChip. A metal plate with holes containing bacterial samples is surrounded by semi-permeable membranes and place in the soil the samples came from.

Before being loaded onto the iChip, the bacteria are diluted so approximately one bacterium cell ends up in each well, allowing scientists to study the growth of an individual bacterium and bacterial species. Because the membranes surrounding the device are semi-permeable, nutrients and anything else specific to the environment can still reach the cells, so the bacteria are tricked into thinking they’re still in their natural environment. This method of bacterial growth manages to get about 50% of the bacteria in the soil sample to grow in a lab culture, a large improvement over the 1% that grow using normal methods [].

How antibiotics work and the novelty of teixobactin

Using the iChip, researchers at Northeastern isolated a new bacterial species from 10,000 new bacteria they found in the soil. They observed that this bacterium, named Eleftheria terrae, could kill other bacteria in its environment. They then determined that its ability to kill off other bacteria comes from a compound it produces. They isolated this compound and named teixobactin [].

In order for an antibiotic to be successful, it must target only bacterial cells so that our human cells are left healthy. Therefore, medically useful antibiotics must attack an important process that occurs in only bacterial cells in order to either kill the cells or inhibit their growth. Penicillin, for example, used to treat a wide variety of diseases, attacks the production of a protein needed to strengthen the cell wall of bacteria, leaving the wall fragile and easily burst open. Ciprofloxacin, which is used to treat anthrax, targets a protein required for bacterial DNA replication, leaving bacterial cells unable to multiply [].

Like penicillin, teixobactin attacks the bacterial cell wall, but unlike penicillin and other common antibiotics, it targets certain fatty lipids instead of proteins. DNA holds the instructions for making proteins, and mutations in DNA can change a protein so that antibiotics cannot recognize it anymore. This is one of the main ways “superbugs” evolve. DNA does not directly encode the directions for making fatty lipids, so genetic mutations are less likely to help bacteria to evolve resistance to teixobactin. Furthermore, since fatty lipids are a fundamental building block of the bacterial cell wall, any mutations that alter them would likely kill the bacterium anyway []. This means teixobactin could successfully treat more bacteria for a longer period of time before bacteria evolve a resistance.

The future of teixobactin and other new antibiotics

So far, this new antibiotic has only been tested in mice. It shows great promise – attacking several common, harmful bacteria, including those that cause tuberculosis, strep, and staph infections, with no signs of developed resistance in any of its targets. The process of approval for human trials is a long way off, however, and it will be even longer before teixobactin can be approved for general use in humans []. While it’s a little too soon to get excited about clinical uses for this antibiotic, the technique these researchers used to discover it offers great potential for more antibiotic discoveries in the near future.

Erin Dahlstrom is a Ph.D. candidate in the Physics Department.

References

[] “The Arms Race Between Germs and Medicine: How Superbugs Have Taken the Lead, and How Humans Can Take It Back.” Vivian Chou, Science in the News.
[] “First global report on antibiotic resistance: reveals serious, worldwide threat to public health.” WHO 2014 report. http://www.who.int/mediacentre/news/releases/2014/amr-report/en/
[] “A new antibiotic kills pathogens without detectable resistance.” Losee Ling et al, Nature. http://www.nature.com/nature/journal/v517/n7535/full/nature14098.html#affil-auth/
[] “U.S. Scientists Discover Powerful New Antibiotic.” Catherine Phillips, Newsweek. http://www.newsweek.com/new-antibiotic-found-dirt-298216/
[] “Promising Antibiotic Discovered in Microbial ‘Dark Matter’.” Heidi Ledford, Scientific American. http://www.scientificamerican.com/article/promising-antibiotic-discovered-in-microbial-dark-matter/
[] “Scientists Hit Antibiotic Pay Dirt Growing Finicky Bacteria In Lab.” Richard Harris, NPR. http://www.npr.org/blogs/health/2015/01/07/375616162/compound-from-soil-bacteria-may-help-fight-dangerous-germs
[] How Products Are Made, Volume 4: “Antibiotic.” Perry Romanowski, How Products Are Made. http://www.madehow.com/Volume-4/Antibiotic.html
[] “The Uncultured Bacteria.” Kim Lewis, Small Things Considered. http://schaechter.asmblog.org/schaechter/2010/07/the-uncultured-bacteria.html
[] Gemma Correll/Anna Goodson Illustration Agency, personal Flickr. https://www.flickr.com/photos/gemmacorrell/8903572877/
[] “How do antibiotics kill bacterial cells but not human cells?.”.Harry Mobley, Scientific American. http://www.scientificamerican.com/article/how-do-antibiotics-kill-b/

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