Lord O'Neill, one of the architects of the so-called Northern Powerhouse, has resigned from the Government.
The former Goldman Sachs chief economist, who also chaired the review into antimicrobial resistance and has just returned from the UN where delegates signed a landmark declaration to tackle the threat, is standing down as Commercial Secretary to the Treasury and quitting the Tory benches in the Lords.
In his resignation letter to the Prime Minister, Lord O'Neill of Gatley said is looking forward "to moving to the cross benches of the Lords".
The UK led a drive to raise global awareness of the threat posed to modern medicine by antimicrobial resistance (AMR).
If antibiotics lose their effectiveness then key medical procedures - including gut surgery, Caesarean sections, joint replacements and chemotherapy - could become too dangerous to perform.
Lord O'Neill said Britain's role in helping to broker the UN agreement on the issue shows the continued importance of the UK on the world stage post-Brexit.
In his letter, he wrote: "Leading this review has been one of the most stimulating roles I have ever undertaken and I am very grateful to all those involved, especially my review team, and all those across Government that allowed the UK to take such a global leadership position in this key threat to the world.
"It goes without saying that our success is symbolic of the way that the UK can be influential in a post-Brexit world."
Lord O'Neill, who also worked to boost trade and investment and on devolution, said he hopes to continue to help support these initiatives in the Lords.
He wrote: "I primarily joined, however, for the specific purpose of helping deliver the Northern Powerhouse, and to help boost our economic ties with key growing economies around the world, especially China and India and other rapidly emerging economies.
"The case for both to be at the heart of British economic policy is even stronger following the referendum, and I am pleased that, despite speculation to the contrary, both appear to be commanding your personal attention.
"I am leaving knowing that I can play some role supporting these critical initiatives as a non-governmental person."
Prime Minister Theresa May said she is "sorry" at Lord O'Neill's resignation and thanked him for his service.
She wrote: "You have made a significant contribution to driving forward the Government's work on delivering growth beyond the South East through the Northern Powerhouse and on promoting stronger economic links with emerging economies, including China and India.
"You have laid important foundations in these areas, and the Government will build on them.
"I would particularly like to pay tribute to your ground-breaking work on Anti-Microbial Resistance. You should take great pride in seeing your review culminate this week in the UN high level agreement.
"You have played a vital role in building global consensus on this important issue which will have long-lasting benefits."