Education secretary nominee Betsy DeVos testifies on Capitol Hill. (Carolyn Kaster/AP)

Sens. Susan Collins (R-Maine) and Lisa Murkowski (R-Alaska) said Wednesday that they intend to vote against the confirmation of President Trump’s education secretary nominee, Betsy DeVos, giving Democrats two of at least three Republican votes they would need to block her appointment.

Republican leaders said that despite the defections, they are confident DeVos will be confirmed.

“She’ll be confirmed — you can take that to the bank,” said Sen. John Cornyn (R-Tex.), the majority whip.

Both Collins and Murkowski said on the Senate floor that while they appreciate DeVos’s efforts to help at-risk children through advocating for vouchers and charter schools, they are concerned that DeVos lacks the experience needed to serve as education secretary and improve public schools, particularly in rural areas. DeVos has no professional experience in public schools, and she did not attend public schools herself or send her own children to them.

“The mission of the Department of Education is broad, but supporting public education is at its core,” Collins said. “I’m concerned that Mrs. Devos’s lack of experience with public schools will make it difficult for her to fully understand, identify and assist with those challenges, particularly for our rural schools in states like Maine.”

Murkowski said children in remote communities across Alaska depend on a strong public school system, and that she isn’t persuaded that DeVos has the background to strengthen that system. As she left the Senate floor, Murkowski said that her decision was the result of an outpouring of responses from Alaskans as well as her own research. “I was trying to get to yes. I just couldn’t,” she said.

A final confirmation vote is expected on the Senate floor either over the weekend or early next week, according to aides to Republican leadership.

There are 48 senators in the Democratic caucus. If they vote as a bloc against DeVos, and if they are joined by Murkowski and Collins, the vote to confirm would be 50-50. In that event, Vice President Pence — a staunch DeVos supporter — would cast the tiebreaking vote. It would mark the first tiebreaking vote by a vice president since Richard Cheney did so nine years ago. Joe Biden, Cheney’s successor, went eight years as vice president without ever breaking a tie.

If a third Republican senator votes against DeVos, she could lose the confirmation vote. Several are facing constituent pressure to oppose the nominee, including Patrick J. Toomey (R-Pa.). “I’m all for her,” Toomey told The Washington Post on Wednesday.

Alaska’s junior senator, Dan Sullivan (R), would not say whether he will vote yes or no on DeVos. But his tone suggested he would lean toward support.

He detailed concerns “similar to what Senator Murkowski was talking about. We have very — almost frontier-type education environments where there’s only one school in the communities. There’s no choice at all.”

“But I’ve had very good meetings with the nominee,” he added. “From my perspective, I think she’s going to be adequately focused on those issues.”

During the White House daily briefing on Feb. 1, press secretary Sean Spicer discussed the confirmation of President Trump's education secretary nominee, Betsy DeVos. (Reuters)

White House press secretary Sean Spicer said the Trump administration has “zero” concerns that DeVos’s nomination will be voted down.

“I am 100 percent confident she will be the next secretary of education,” Spicer said at Wednesday’s news briefing.

Trump’s nomination of DeVos, a Michigan billionaire and major donor to Republican causes, has triggered a sharp partisan battle, and she has faced an unprecedented level of opposition for a prospective education secretary. Both of the nation’s largest teachers unions mounted campaigns against her immediately after her nomination, but opposition broadened after she stumbled over basic education policy questions during her Jan. 17 confirmation hearing. Parents and teachers have flooded the Senate’s phone lines and email inboxes in recent weeks, urging senators to vote against DeVos.

“The nation is speaking out.… Senators need to listen,” said Lily Eskelsen Garcia, president of the National Education Association.

Several previous education secretary nominees were confirmed on a voice vote or by unanimous consent. The deepest division to date was over the nomination of John B. King Jr., who was confirmed in March 2016 on a 49-40 vote. Even then, key Republicans — including Lamar Alexander (Tenn.), chairman of the Senate Education Committee, and Mitch McConnell (Ky.), the majority leader — voted in King’s favor, giving his confirmation a bipartisan blessing.

Kelsey Snell, Paul Kane and Ed O’Keefe contributed to this report.