Boris Johnson is facing a 'red wall' revolt with over 50 Tory MPs demanding a tailored recovery plan for the North.
The demands come as the Government prepares to plunge eight million people into the toughest coronavirus restrictions.
Downing Street officials have confirmed four separate parts of Nottinghamshire will be subjected to Tier 3 lockdowns from midnight on Wednesday - the latest region in England to be imposed with the severest restrictions.
A letter to the PM from the newly-formed alliance of Conservative MPs the Northern Research Group demands a post-pandemic economy plan and a roadmap out of lockdown.
Group leader Jake Berry, the former Northern Powerhouse minister, fears the North-South divide will only get wider and send the North "into reverse" unless decisive action is taken.
NRG is urging the Government to "level-up the North", making assurances for key infrastructure projects and help create jobs - something Johnson promised after making huge gains in various Labour northern strongholds during December's landslide election win.
Following days of crunch talks with ministers, leaders in Nottingham City, Gedling, Broxtowe and Rushcliffe have agreed to be thrust into draconian lockdowns.
The measures are expected to be officially announced on Tuesday.
Pubs and bars will be shut, except for those serving meals, and mixing indoors or in private gardens with those outside of households will be banned.
MP for Rossendale and Darwen, Mr Berry, told the Daily Mail: "The virus has exposed in sharp relief the deep structural and systemic disadvantage faced by our communities and it threatens to continue to increase the disparity between the North and South still further.
"Our constituents have been some of the hardest hit by this virus with many losing jobs, businesses, and livelihoods. Never has there been a more pertinent and urgent political and economic case to support people living in the North.
"However, instead of moving forwards on our shared ambitions, the cost of Covid and the virus itself threatens to send the North into reverse."
It comes just hours after Warrington was put into Tier 3 amid a case surge among over-60s, as Health Secretary Matt Hancock insisted it's "time to take action" and "sacrifices must be made".
Labour's Nottingham East MP Nadia Whittome said the situation was "totally avoidable" if track and trace had been improved and extra financial support was afforded earlier on.
She added Nottingham City Council has made it clear the Government's proposals "are not adequate", adding it must "urgently change its attitude" towards the city's MPs and agree to "get round the table with us".
Those to publicly sign the NRG letter include former Tory Cabinet ministers David Davis and Esther McVey, as well prominent backbenchers Philip Davies and Ben Bradley.
Conservative MP for Hazel Grove in Greater Manchester, William Wragg, said the pandemic has "exacerbated" the need for a "good deal for the North".
"On a pan-northern basis, we can work with government to create wealth and opportunity for our constituents, building back better after Covid," he told Sky News.
Forty Conservative MPs have publicly signed the letter, while a further 14 have had their names redacted.
Mr Johnson won a majority of 80 seats at last year's general election, turning many traditional Labour constituencies - which formed the so-called Red Wall - blue.
Many Tories fear the seats will return to Labour in the next election unless the PM acts.