Furious Boris Johnson hit back at Greater Manchester Mayor Andy Burnham for refusing to agree to Tier 3 restrictions.
The Prime Minister insists measures are "about saving lives" and that he would "rather not impose things" in the region.
Boris called on local leaders to "show the kind of leadership seen in Liverpool, Lancashire and London" in an angry dig at Burnham.
Speaking to reporters on Friday afternoon, the PM said: "Clearly if you're going to enforce these measures, if you're going to do proper local testing and tracing, if you're going to get local buy-in and compliance, local leadership is crucial and we want to work with local leaders.
"I am, I have to say, concerned about what's happening in Manchester where the levels of infection are rising steeply, the level of hospitalisation is rising steeply and we do need to see action.
"I'd much rather not impose things, I'd much rather that we were able to work out something together with local authorities, with the mayor in Manchester.
"But it is up to local leaders to show the kind of leadership that we have seen in Liverpool, in Lancashire and in London."
Despite Burnham's resistance, it is reported Boris may press ahead and force the restrictions on the area.
On Thursday Greater Manchester mayor Andy Burnham accused the government of treating the region as "a canary in the coal mine" as he called for more financial support for businesses and workers hit by potential restrictions.
But Mr Johnson hit back, insisting his measures are about reducing Britain's crippling death toll.
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He told reporters: "As I say, other local leaders have come forward and joined in the tiering system, showing the kind of leadership that I think is necessary.
"This is about saving lives.
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"This is about us joining together locally and nationally to get the R down, to make these regional restrictions, this tiering system, work and to save lives.
"Everybody in Greater Manchester and all the areas that are still finding it difficult should think about it."
It comes after foreign secretary Dominic Raab accused Mr Burnham of trying to "hold the government over a barrel over money and politics" by resisting tougher restrictions and urged him to "do the right thing by the people of Manchester".
Mr Burnham, responding on Twitter, said: "It's not about what we want for ourselves, Dominic Raab.
"It's about what we want for low-paid and self-employed people everywhere: fairness."
It emerged earlier on Friday that Lancashire will also be placed under a Tier 3 lockdown.
From Saturday, people in the north west county will be banned from socialising with anybody they do not live with in any indoor setting or private garden, as well as in most outdoor hospitality venues.
All pubs and bars must close unless they are serving substantial meals, and casinos, bingo halls, bookmakers, betting shops, soft play areas and adult gaming centres will be forced to shut.
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