Boris Johnson is facing a furious backlash after Britain's ambassador to the US quit following the leak of diplomatic dispatches critical of Donald Trump's White House.
Sir Kim Darroch said he was leaving his post early as it had become "impossible" for him to carry out his duties effectively in the wake of the firestorm over his private advice to ministers.
It followed a tirade of abuse by Mr Trump who branded him a "very stupid guy" and a "pompous fool" and said the administration would have no further dealings with him.
Sir Kim's position came under further pressure after Mr Johnson, the Tory leadership front runner, repeatedly refused to back him in Tuesday's televised debate.
Foreign Office Minister Sir Alan Duncan angrily accused Mr Johnson of having thrown Sir Kim "under a bus" to further his own leadership ambitions.
Meanwhile Downing Street confirmed that "initial discussions" had taken place with the police regarding the Whitehall investigation into the source of the leak.
"If there was concern about criminal activity, the police would become involved more formally at that point," a No 10 spokeswoman said.
Mr Johnson expressed his regret at Sir Kim's departure, describing him as a "superb diplomat" who he had worked with for many years.
"It is not right that civil servants' careers and prospects should be dragged into the political agenda," he said.
His comments were dismissed as "insincere guff" by Sir Alan - a long-standing critic of the former foreign secretary - who said he had deliberately failed to give Sir Kim his support during the debate.
"For someone who wants to lead, let alone unite, the country, that was contemptible negligence on his part," he told the BBC.
"He has basically thrown this fantastic diplomat under the bus to serve his own personal interests."
Sir Nigel Sheinwald, a former ambassador to the US, said he believed Mr Johnson's comments may have played a part in Sir Kim's decision to go.
"I don't think he got the support he needed from across our political class. I am sure that those comments by Boris Johnson may well have played a factor in his ultimate decision to resign," he told BBC Radio 4's The World at One.
"I think that what worried him was what would happen with a new prime minister who had made no commitment to him at all in the debate last night."
Shadow foreign secretary Emily Thornberry said Mr Johnson should "hang his head in shame" over his failure to support Sir Kim.
"The fact that Sir Kim has been bullied out of his job, because of Donald Trump's tantrums and Boris Johnson's pathetic lick-spittle response, is something that shames our country," she said.
In his letter of his resignation, Sir Kim said he wanted to put an end to the speculation surrounding his position following the leak of cables in which he described the Trump administration as "inept" and "dysfunctional".
"The current situation is making it impossible for me to carry out my role as I would like," he said.
"Although my posting is not due to end until the end of this year, I believe in the current circumstances the responsible course is to allow the appointment of a new ambassador."
In the Commons, Theresa May told MPs Sir Kim's departure was a "matter of great regret" while pointedly stressing the importance of backing public servants when they come under pressure.
"The whole Cabinet rightly gave its full support to Sir Kim on Tuesday," she said.
"Good government depends on public servants being able to give full and frank advice.
"I want all our public servants to have the confidence to be able to do that and I hope the House will reflect on the importance of defending our values and principles, particularly when they are under pressure."
Earlier, Health Secretary Matt Hancock, a leading supporter of Mr Johnson, defended his refusal to support Sir Kim, saying it was important to repair relations with the White House.
"It is our most important diplomatic relationship," he said.
"Whoever is the president of the United States, we have to have a strong relationship with them."
The difficulties facing Sir Kim following Mr Trump's outburst became apparent when he was "uninvited" to a White House dinner in honour of the Emir of Qatar.
He also reportedly chose to stay away from a meeting between International Trade Secretary Liam Fox and the president's daughter, Ivanka, to avoid any potential embarrassment.
It then emerged a planned meeting between Mr Fox and the US commerce secretary - which Sir Kim had also been expected to attend - was cancelled due to "diary clashes".
Mr Johnson's rival for the Tory leadership, Foreign Secretary Jeremy Hunt - who made a point of supporting Sir Kim in the debate - praised his "unswerving devotion" to upholding UK interests.
"He brought dispassionate insight and directness to his reporting to ministers in London," he said.
"I profoundly regret how this episode has led Sir Kim to decide to resign."