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Northeastern receives $9M grant to fast track the discovery of new antibiotics

by Thea Singer

In Sep­tember 2014, Pres­i­dent Obama issued an exec­u­tive order for “Com­bating Antibiotic-​​Resistant Bac­teria.” Why the urgency? The Cen­ters for Dis­ease Con­trol and Pre­ven­tion, the order noted, “esti­mates that annu­ally at least 2 mil­lion ill­nesses and 23,000 deaths are caused by antibiotic-​​resistant bac­teria in the United States alone.”

This month, a team led by North­eastern Uni­ver­sity Dis­tin­guished Pro­fessor of Biology Kim Lewis received a five-​​year, $9 mil­lion grant from the National Insti­tutes of Health’s National Insti­tute of Allergy and Infec­tious Dis­eases to develop a novel plat­form to trans­late the president’s order into action.

The award will enable the team to expand on the pio­neering research of Lewis and Dis­tin­guished Pro­fessor of Biology Slava Epstein. The pair used an inno­v­a­tive method to grow “uncul­tur­able” bac­teria in the lab, leading to the dis­covery of a new antibi­otic that kills pathogens without encoun­tering any detectable resis­tance. Called teixobactin, the antibi­otic elim­i­nated the superbug MRSA, or methicillin-​​resistant Staphy­lo­coccus aureus, in mice as well as numerous other pathogens.

The new plat­form will facil­i­tate quick iden­ti­fi­ca­tion of new antibi­otics such as teixobactin, says Lewis, who is also director of the Antimi­cro­bial Dis­covery Center. “There are a number of bot­tle­necks in nat­ural product dis­covery,” he says. “Our aim is to resolve these bot­tle­necks and improve our effi­ciency by a couple of orders of magnitude.”

Indeed, as the authors write in a paper they recently sub­mitted, the plat­form “has strong poten­tial to return us to the golden age of antibi­otic discovery.”

The well runs dry

In that golden age, researchers dis­cov­ered new antibi­otics by screening soil for microor­gan­isms that pro­duced com­pounds lethal to other pathogens. But that well essen­tially ran dry by the late 1960s, and the bac­teria had acquired muta­tions that ren­dered them resis­tant to the once effec­tive antibiotics.

Lewis and Epstein’s break­through was in finding a way to tap into the 99 per­cent of soil-​​based microor­gan­isms that won’t grow in a lab. They used a small device devel­oped by Epstein’s group called the iChip that iso­lates and grows indi­vidual bac­te­rial cells in their nat­ural soil envi­ron­ment. The break­through led to Lewis and Epstein co-​​founding Novo­Bi­otic Phar­ma­ceu­ti­cals, in Cam­bridge, Mass­a­chu­setts. Amy Spo­ering, PhD’05, who now works at Novo­Bi­otic, is a co-​​investigator on the new NIAID grant. From the uncul­tured bac­teria they iden­ti­fied 25 new antibi­otics, among them teixobactin and las­somycin, which acts against Mycobac­terium tuberculosis.

Still, says Lewis, the process left cer­tain ele­ments up to chance. “We had no idea whether the soil har­bored inter­esting microor­gan­isms or didn’t,” he says. “So then the obvious ques­tion became: Why not take a step back and screen the soils them­selves before iso­lating indi­vidual bacteria?”

On the fast track to discovery

The new plat­form uses sophis­ti­cated genomic tech­nolo­gies and bioin­for­matics tools to do just that.

With co-​​investigator Karen E. Nelson, pres­i­dent of the J. Craig Ventor Insti­tute, in La Jolla, Cal­i­fornia, the researchers will extract DNA straight from the soil sam­ples and, using genetic sequencing, deter­mine the diver­sity of the microor­gan­isms within and iden­tify each one by type.

It’s a one-​​step process,” says Lewis. “Based on expe­ri­ence we will then know right away whether the soil con­tains the types of bac­teria that have his­tor­i­cally been linked to antibi­otic production.”

The ini­tial soil sam­ples, says Lewis, will come from North­eastern prop­erty, including that in Nahant, Mass­a­chu­setts, home of the university’s Marine Sci­ence Center.

Cur­rently, once researchers iden­tify a promising bac­terium based on its ability to inhibit a pathogen, say, MRSA, they take an extract from it and chem­i­cally ana­lyze the extract’s char­ac­ter­is­tics. “It’s a labo­rious process, an enor­mous bot­tle­neck,” says Lewis. “And the vast majority of things found in pro­ducing bac­teria are junk. Finding a com­pound that’s useful is like searching for a needle in a haystack.”

The new plat­form fast-​​tracks the process. The extracts will be ana­lyzed not chem­i­cally but bio­log­i­cally, dis­playing what genes the target pathogen expresses when treated with an extract con­taining an antimi­cro­bial com­pound. “From that pat­tern of gene expres­sion we can deduce the mode of action of the com­pound and make a call about its poten­tial use­ful­ness,” says Lewis.

Finally, Lewis will test the selected com­pounds to map their mech­a­nism of action in detail and then val­i­date their effec­tive­ness against a host of pathogens both in cell cul­tures and a mouse model.

I think that we are going to find many novel antibi­otics,” says Lewis. “We are very excited about this opportunity.”

Originally published in news@Northeastern on July 11, 2016.

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