Uncovering science’s secret weapon of antibiotic discovery: The iChip

Let’s play a game: do you think more people have died of the Ebola virus in West Africa, or an everyday infection? Although Ebola may be a tempting answer,  bacterial and fungal infections have become exceedingly deadly over the past few years. According to the Centers for Disease Control, fewer than 9,000 people have died of Ebola in the past year, while over 2 million people in the U.S. alone have developed serious infections and at least 23,000 of those people have died as a direct result. Many others have died from other medical conditions that were further complicated by infections. 

These alarming statistics seem to magnify the increasing trend of antibiotic resistance. Antibiotic resistance occurs when microbes – or bacteria, viruses, fungi and parasites – acquire a genetic mutation that prevents drugs from affectively killing the microbes. Over time, these robust microbes transfer their antibiotic resistant genes to nearby microbes, which continuously facilitates the spread of antibiotic resistance.

The spread of antibiotic resistance limits the effectiveness of drugs and has caused a massive public health scare. This has prompted scientists to consistently discover and introduce new compounds. During the early era of drug discovery, scientists traditionally found most antibiotics by cultivating soil bacteria. Despite many years of success, overmining soil bacteria has resulted in the collapse of drug discovery from natural environments.

Scientists stopped discovering useful soil bacteria decades ago because they did not have the proper technology to examine the bacteria in situ (within their natural environment). This limited their search to bacterial species that could be readily cultured, or grow under laboratory conditions. Uncultured bacteria were out of the picture.

However, uncultured bacteria make up approximately 99% of all bacterial species in natural environments. This enticing statistic has urged scientists to come up with new technologies to examine uncultured bacteria. According to the K. Lewis of Northeastern University, this technology is possible and already being put to use. Lewis and his colleagues developed a method of growing uncultured microbes within their natural environment. With this new method, they discovered a new antibiotic they termed teixobactin that kills pathogens without any known, detectable resistance. Lewis and his team suggest that it will take over 30 years for bacteria to become resistant to teixobactin.

Although that news is exciting within itself, the research community is even more excited about the technique used to examine teixobactin: the iChip. In 2010, the iChip was first developed by D. Nichols of Northeastern University and then borrowed by Lewis for experimentation purposes. Nichols and his team built off of their earlier method of in situ cultivation, where microbes thrived inside diffusion chambers containing naturally occurring growth factors. They utilized this design and complied the miniature diffusion chambers onto an isolation chip – or iChip, for short.

iChip configuration. http://www.nature.com/nature/journal/v517/n7535/full/nature14098.html

In order to successfully grow the soil microbes, Nichols assembled a flat plate containing uniform holes (a) and then dipped the plate into a suspension of mixed cells. Each hole captured a single cell (b), which was then sealed with semi-permeable membranes (c). The iChips were then returned to their natural environments, and this case waterlogged soil. This process allowed microbes to easily absorb nutrients and growth factors from their natural environments. After 2 weeks, Nichols and his team identified the microbes using genetic sequencing and compared their results to microbial growth on petri dishes.

iChip in the field - Slava Epstien/ Northeastern University

http://www.forbes.com/sites/judystone/2015/01/08/teixobactin-and-ichip-promise-hope-against-antibiotic-resistance/

They discovered that the microbes within the iChip grew approximately 30% larger colonies compared to the petri dishes. The iChip also exhibited 94-97% genetic similarities to known bacterial species, which means there is a 3-6% chance of novel microbial discovery. In comparison, the soil bacteria cultivated on petri dishes resembled 97-100% identity with previously cultivated species. Although these numbers may seem insignificant, the provide big hope to the science community in conquering antibiotic resistance. 

Microbe colonies from iChip under microscope - http://aem.asm.org/content/76/8/2445.full#aff-1

The ability of the iChip to cultivate novel microbes is exceedingly desirable to scientists because new antibiotics are less likely to experience a rapid rise in resistance (as seen in Lewis teixobactin). This spectacular diversity of microbes will slow down – and hopefully stop – antibiotic resistance right in its tracks.

1) Lewis, Kim (2012). Antibiotics: Recover the lost art of drug discovery. Nature. 485, 439-440.

2) Ling, L. L. (2015). A new antibiotic kills pathogens without detectable resistance. Nature. 485, 455-459.

3) Nichols, D. (2010). Use of Ichip for High-Throughput In SituCultivation of “Uncultivable” Microbial Species. Applied and Environmental Microbiology. 76(8), 2445-3450.