How to treat a leading cause of potentially fatal hospital-acquired infections?

TORONTO, ON — Researchers at the Uni­ver­si­ty of Toron­to have dis­cov­ered that Can­di­da albi­cans – a lead­ing cause of poten­tial­ly fatal hos­pi­tal-acquired infec­tions – rarely devel­ops resis­tance to com­bi­na­tion drug ther­a­py and, when it becomes resis­tant, it also becomes less dan­ger­ous.

The team may also have found a new way to elim­i­nate Can­di­da albi­cans in humans.

Treat­ing fun­gal infec­tions through a sin­gle drug is increas­ing­ly inef­fec­tive because fun­gi quick­ly evolve drug resis­tance. Com­bi­na­tion ther­a­pies have shown great promise in over­com­ing this prob­lem, but sci­en­tists are con­cerned these com­bi­na­tions will spur even stronger resis­tance.

By test­ing com­bi­na­tion ther­a­pies in Can­di­da albi­cans, the U of T researchers found that only a few strains of this fun­gus became drug-resis­tant, and that resis­tance came at a cost to the fun­gus.

“Drug resis­tance in fun­gal infec­tions is a huge prob­lem,” says Pro­fes­sor Leah Cowen, the lead researcher on the study who holds the Cana­da Research Chair in Micro­bial Genomics and Infec­tious Dis­ease in U of T’s depart­ment of mol­e­c­u­lar genet­ics. “And if we’re going to treat these infec­tions with drug com­bi­na­tions we need to know if they’ll read­i­ly become resis­tant. In Can­di­da albi­cans we found a trade-off: a few strains gain some resis­tance but they become less ‘fit’ or func­tion­al when the drug is not present.”

Professor Leah Cowen, lead researcher on the study and Canada Research Chair in Microbial Genomics and Infectious Disease in U of T’s department of molecular genetics (Photo courtesy of NSERC)

The strains of the yeast that became resis­tant to drug com­bi­na­tions grew poor­ly in sev­er­al stress con­di­tions which are con­nect­ed to human infec­tions. For exam­ple, the resis­tant strains became weak­er when they encoun­tered oxida­tive stress, which hap­pens when peo­ple become sick.

The researchers also found that resis­tant strains were vul­ner­a­ble to immune cells called macrophages – fur­ther evi­dence that drug com­bi­na­tions may min­i­mize drug resis­tance.

Cowen and her col­leagues used Can­di­da albi­cans strains they cre­at­ed in the lab, and they com­pared them to strains that were sen­si­tive to com­bi­na­tion ther­a­py. They also con­firmed their find­ings with yeast that had evolved resis­tance in a patient. “This was an impor­tant step, because what you learn in a test tube often doesn’t cor­re­spond to what hap­pens in a patient,” says Cowen.

The jour­nal Cell Reports pub­lished the find­ings.

Can­di­da albi­cans is the third-lead­ing cause of intravas­cu­lar catheter-relat­ed infec­tions, and when acquired from implant­ed med­ical devices, it kills one-third of peo­ple it infects. The num­ber of fun­gal blood­stream infec­tions has more than dou­bled over the last two decades, part­ly because suc­cess­ful treat­ments for can­cer and AIDS have left many patients immune-com­pro­mised and vul­ner­a­ble to infec­tion.

Cowen and her lab have devel­oped a com­bi­na­tion ther­a­py for Can­di­da albi­cans that inhibits a pro­tein in the yeast called Heat-shock pro­tein 90 (Hsp90). They’re eager to test the ther­a­py in patients, espe­cial­ly giv­en Candida’s lim­it­ed resis­tance to it. But a big chal­lenge is that Hsp90 is also an impor­tant pro­tein in humans, so they need to devel­op fun­gal-selec­tive inhibitors that tar­get it in yeast exclu­sive­ly.

Recent­ly, they found a way to do that.

Cowen’s team cre­at­ed and com­pared detailed maps of the drug-bind­ing struc­ture of Hsp90 in Can­di­da albi­cans and in humans. In the yeast, the Hsp90 pro­tein con­tains a larg­er pock­et through which drugs can bind to it. So by increas­ing the size of the drug-like mol­e­cules, they engi­neered a poten­tial ther­a­py that tar­gets Hsp90 only in yeast – the mol­e­cules are too big to bind in the Hsp90 drug-bind­ing pock­et in peo­ple.

“It seems to work,” says Cowen. “We have a hand­ful of struc­tures that pref­er­en­tial­ly inhib­it the fun­gal pro­tein over the human coun­ter­part. With a lit­tle more fund­ing we can improve on these mol­e­cules and ulti­mate­ly test this treat­ment in patients.”

-30-

For more infor­ma­tion, please con­tact:

Suniya Kukaswa­dia
Com­mu­ni­ca­tions Assis­tant
Office of Strat­e­gy, Com­mu­ni­ca­tions and Exter­nal Rela­tions
Uni­ver­si­ty of Toron­to Temer­ty Temer­ty Fac­ul­ty of Med­i­cine
Office: 416–978-7752
suniya.kukaswadia@utoronto.ca