Northeastern researchers work to keep hospital-​​acquired staph infections in check

by Thea Singer

Hospital-​​related staph infec­tions are ram­pant. In 2005 alone there were an esti­mated 478,000 cases in the U.S., according to the Cen­ters for Dis­ease Con­trol and Pre­ven­tion. The num­bers are drop­ping, the agency recently reported in a release, “but more work is needed.”

A team led by Kim Lewis, Uni­ver­sity Dis­tin­guished Pro­fessor and director of Northeastern’s Antimi­cro­bial Dis­covery Center, is at the fore­front of that work.

Staphlo­coccus aureus, the bac­terium behind the infec­tions, evades antibi­otics, causing serious chronic or relapsing dis­eases including endo­carditis and osteomyelitis. In a new paper pub­lished in the journal Nature Micro­bi­ology, Lewis and his col­leagues reveal the reason behind that evasion.

The researchers zeroed in on a sub­pop­u­la­tion of bac­te­rial cells called “per­sis­ters,” in the process leading the way to new drugs to kill them.

Formed by all pathogens, per­sis­ters are living cells that exist in a dor­mant, spore­like state. Because con­ven­tional antibi­otics attack only actively func­tioning bac­te­rial cells, per­sis­ters sur­vive their onslaught. But once the antibi­otic has been flushed from the system, the per­sis­ters “wake up” and mul­tiply, rein­fecting the host.

We found that nothing that we or anyone else had learned from E. coli or other bac­teria applied to staph,” says Lewis, who dis­cov­ered per­sis­ters’ role in relapsing infec­tions in 2000. Staph, says Lewis, had a “com­pletely new” mech­a­nism for per­sister for­ma­tion. Loss of energy shut the staph cells down.

I think what we dis­cov­ered is a gen­eral mech­a­nism of per­sister for­ma­tion that likely oper­ates in all bac­teria but has been over­looked,” says Lewis.

Energy: the force of life

From a mol­e­c­ular stand­point, that mech­a­nism is a drop in the chem­ical adeno­sine triphos­phate, or ATP, “the energy cur­rency” of the cell, explains Brian P. Conlon, a senior research sci­en­tist at North­eastern. Conlon is joint first author of the paper with Sarah E. Rowe, a former post­doc­toral research asso­ciate in Lewis’ lab.

Addi­tional researchers from North­eastern, as well as from the Geisel School of Med­i­cine at Dart­mouth Col­lege and the Pacific North­west National Lab­o­ra­tory, con­tributed to the paper.

ATP stores the energy a cell needs to do every­thing from growing to repro­ducing. In staph, the researchers found, when nutri­ents and oxygen became scarce due to an expanding pop­u­la­tion, ATP levels plum­meted and many for­merly active bac­te­rial cells entered a phase that mir­rors the per­sister state, making them immune to antibiotics.

The cells low in ATP were a thousand-​​fold more likely to sur­vive an antibi­otic chal­lenge than those with reg­ular levels of ATP,” says Conlon. “This tells us that the energy level of the cell pre­dicts whether the cell will live or die when it’s treated with antibiotics.”

A drug built for persisters

The finding sheds light on why the antibi­otic ADEP4, a deriv­a­tive of the drug acyldep­sipep­tide that Lewis is devel­oping with Ari­etis Phar­ma­ceu­ti­cals, is so effec­tive at killing staph, and may be just as effec­tive against other drug-​​tolerant pathogens.

Con­ven­tional antibi­otics, such as peni­cillin and ciprofloxacin, require bac­te­rial cells to be actively func­tioning in order to work; that means cells with lots of ATP. ADEP4, on the other hand, works in the absence of ATP, making it a per­fect fit for those dor­mant, low-​​ATP per­sister cells.

To prop­erly treat per­sis­ters you need com­pounds that are going to kill the cell by a mech­a­nism that doesn’t depend on the avail­ability of ATP,” says Lewis.

How does ADEP4 operate? It first binds to an enzyme in the bac­te­rial cell whose job is to digest pro­teins that have gone bad—think of a cel­lular garbage col­lector, says Lewis. In so doing, it essen­tially trans­forms the enzyme into an evil doppelgänger—the enzyme now forces both growing and dor­mant cells to self–digest.

ADEP4 is an example of how under­standing the cause of antibi­otic tol­er­ance can lead to devel­oping drugs that will directly kill these cells,” says Conlon.

Originally published in news@Northeastern on April 25, 2016.

Kim Lewis, professor of biology, and post-doctoral researcher Brian Conlon work in Lewis' lab.

Kim Lewis, professor of biology, and post-doctoral researcher Brian Conlon work in Lewis’ lab.

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