LONDON — Prime Minister Boris Johnson on Saturday suffered a serious new blow at the end of a week of turmoil in British politics when his close ally and negotiator on Brexit, David Frost, announced his resignation, citing differences over the direction of government policy.

Mr. Frost, a member of the cabinet, was a leading architect of the country’s Brexit agreement and was engaged in difficult negotiations with the European Union over how the country’s exit terms applied to Northern Ireland.

In his letter of resignation, Mr. Frost, who is a member of the House of Lords, said that Brexit was “secure” but that the prime minister was aware of his “concerns about the current direction of travel,” hinting at differences over policy since Britain quit the European Union.

He added: “I hope we will move as fast as possible to where we need to get to: a lightly regulated, low-tax, entrepreneurial economy at the cutting edge of modern science and economic change.”

The announcement of his departure, which he said in his letter would be effective immediately, heaps new pressure on Mr. Johnson, whose leadership has been called into question by a succession of recent setbacks just as Britain combats a new wave of coronavirus infections. Mr. Frost’s resignation had been reported earlier in the day by The Mail on Sunday.

Mr. Frost, who according to surveys is very popular among Conservative Party members, also hinted in his letter that he had significant differences with Mr. Johnson over coronavirus restrictions: “We also need to learn to live with Covid and I know that is your instinct too,” he wrote. “You took a brave decision in July, against considerable opposition, to open

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