Researchers on fast track to combat antibiotic resistance

The mar­riage of two inno­v­a­tive technologies—one devel­oped by Northeastern’s Slava Epstein, the other by the Broad Institute’s Paul Blainey—could accel­erate both the dis­covery of new antibi­otics that kill pathogens without encoun­tering resis­tance and the diag­nosis of spe­cific pathogens causing dis­ease, enabling fast, tar­geted treatments.

The new system, described in a paper in the journal Nature Com­mu­ni­ca­tions, speaks to the Obama administration’s recent release of a National Action Plan to Combat Antibi­otic Resis­tant Bac­teria that calls for nation­wide tracking of antibi­otic resis­tance in pathogens using DNA sequencing.

Why DNA sequencing? Because it reveals a pathogen’s every move, whether offen­sive or defensive.

Four chem­ical com­pounds, called “bases,” make up the DNA of organ­isms from bac­teria to us. The order, or sequence, of those bases deter­mines the organism’s genetic inher­i­tance. Taken together, the ordered bases—the “genome”—spell out the instruc­tions for making and main­taining the entire organism. In the case of a bac­terium, a par­tic­ular sequence might code for a nat­ural com­pound that kills other bac­teria or, con­versely, one that ensures its sur­vival in the face of an attack from others. The killer com­pound could be a can­di­date for a new antibi­otic, the pro­tector com­pound the source of a bacterium’s antibi­otic resis­tance, let­ting clin­i­cians know which drugs not to pre­scribe if it hits.

The research team’s new lab-​​on-​​a-​​chip per­mits the screening of not only many more pathogens in record time at lower cost but also mul­ti­tudes of pathogens that until now have not been avail­able for analysis.

The plat­form addresses the bot­tle­neck in the overall sequencing of the genome, that is, the prepa­ra­tion of the DNA itself,” says Epstein, Dis­tin­guished Pro­fessor of Biology. “In the past, researchers had to grow mas­sive amounts of bac­teria and extract, purify, frag­ment, tag, and sort mas­sive amounts of DNA from them, a costly and time-​​consuming process. This new system reduces the amount of DNA required 100-​​fold. We can use a tiny amount of cells—even 10,000 is enough—and pro­duce supe­rior sequencing analyses.”

A meeting of minds

Blainey’s lab at the Broad Insti­tute of the Mass­a­chu­setts Insti­tute of Tech­nology and Har­vard devel­oped the fun­da­mental tech­nology: a tool that auto­mates the steps nec­es­sary to pre­pare the DNA for sequencing using just minus­cule amounts of each liquid sample. It employs the sci­ence of “microfluidics”—the flow of liq­uids, usu­ally in the range of micro­liters (one-​​millionth of a liter) to pico­l­iters (one-​​trillionth of a liter), through micrometer-​​size channels.

Epstein’s iChip device expands the reach of Blainey’s tech­nology immea­sur­ably. The iChip iso­lates and grows small colonies of indi­vidual bac­te­rial cells in their nat­ural soil envi­ron­ment, per­mit­ting researchers to access the 99 per­cent of soil-​​based microor­gan­isms that won’t grow in a lab, the so-​​called micro­bial dark matter.

In the past, researchers dis­cov­ered new antibi­otics by screening soil teeming with bac­teria in the lab to find which ones pro­duced com­pounds lethal to other bac­teria. But today many bac­teria, such as Staphy­lo­coccus aureus, have acquired muta­tions that render them resis­tant to cur­rent antibi­otics. With the well of cul­tur­able bac­teria essen­tially run dry, Kim Lewis, Uni­ver­sity Dis­tin­guished Pro­fessor of Biology, and Epstein cofounded the Cambridge-​​based biotech­nology com­pany Novo­bi­otic Phar­ma­ceu­ti­cals to plumb the micro­bial dark matter, with iChip in hand. There, they and their col­leagues dis­cov­ered teixobactin, a new antibi­otic that kills pathogens without encoun­tering resis­tance. They are on the fast track to dis­cover more.

With this plat­form, we can do high-​​throughput screening of genomes of cul­tur­able and of pre­vi­ously uncul­tur­able bac­teria,” says Epstein. The paper describes suc­cess at sequencing both types accu­rately and quickly: The known pathogens Mycobac­terium tuber­cu­losis, whose slow growth stalls its diag­nosis, and Pseudomonas aerug­i­nosa, and new soil micro­colonies pro­duced via the iChip.

The find­ings address a crit­ical con­cern of the recent Report to the Pres­i­dent on Com­bating Antibi­otic Resis­tance, which notes: “CDC has a large repos­i­tory of well-​​characterized bac­te­rial pathogens, but few have been sequenced to date.”

They also directly address patients’ needs. Given the very small sam­ples the system requires, indi­vid­uals could ben­efit from rapid by-​​the-​​bedside testing to diag­nose the par­tic­ular pathogens causing their dis­ease as well as which antibi­otics the sequenced pathogen might be resis­tant to.

The high-​​throughput and high-​​accuracy sample prepa­ra­tion method pre­sented here is posi­tioned to power pre­ci­sion med­i­cine, genomic sur­veil­lance, antibiotic-​​resistance tracking, and novel organism/​natural product dis­covery on large scales,” the authors conclude.

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