The Republicans party, which was expected to win this year's presidential and national assembly elections, will hold the first round of a leadership contest on Sunday which Wauquiez is seen as almost certain to win.
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His emergence, which will shift the party closer to the far-right National Front, is the latest act in the redrawing of France's political map sparked by Macron's sensational victory at the head of a centrist party this year.
Wauquiez, leader of the southeastern Auvergne-Rhone-Alpes region and a former mayor, MP and minister, is expected to easily see off two little-known rivals for the top job -- but he does not have unanimous support.
"By running after the National Front, we will end up by giving the far-right power," Franck Riester, a former Republicans lawmaker who has broken away from the party, said recently.
Macron, unknown to the public until he became economy minister in 2014, ran as an independent this year and then oversaw a thumping victory for his Republic on the Move party in parliamentary elections in June.
Since then, the traditional parties of government -- the Republicans and the Socialists -- have been ineffective in opposition, while the National Front and hard-left France Unbowed party have struggled to make an impact.
Having seen his approval ratings slide faster than any other previous president in his first months in office, the 39-year-old Macron has since recovered some of his popularity thanks to his pro-business reforms and hyperactive diplomacy.
A new poll by the Ifop group this week showed 50 percent of respondents were happy with his performance, up from the low-30s in November.
'French Trump?'
Wauquiez will inherit a party that has traditionally represented the dominant centre-right force in French politics which groups centrists, liberals as well as hard-right conservatives.
But it has suffered the spectacular fall from grace of its presidential nominee Francois Fillon, who finished third after a fake jobs scandal involving his wife and children.
Macron also lured away many centre-right voters and then raided the Republicans for ministerial material, wooing Prime Minister Edouard Philippe and Budget Minister Gerald Darmanin among others.
Describing the disarray within the party, which is the biggest opposition party in parliament, Wauquiez told Le Parisien daily the party was in "ruins" after Fillon's stinging defeat.
The boyish but grey-haired candidate, who was elected MP at age 29 and became a minister in his early thirties, sees the solution as making the Republicans "truly right-wing" on immigration, security and sovereignty.
The president of the National Assembly, Francois de Rugy, a member of Macron's Republic on the Move (LREM) party, has accused him of "acting like a French Trump".
'Ideal candidate'
Philippe Braud, professor emeritus at Sciences-Po University in Paris, said Wauquiez's uncompromising approach made him the "ideal candidate" to position the Republicans for a comeback.
With Macron monopolising the centre ground, Braud said, "the Republicans can only survive if they tack to the right."
But in doing so Wauquiez risks leading a rump of a party sandwiched between the National Front and Macron's centrists.
"He will inherit a crown without a kingdom, a party without partisans," National Front leader Marine Le Pen said at the weekend.
Many of the moderate Republicans lawmakers have broken away to form "Agir" ("Act"), which supports the president's agenda, while Macron continues to make inroads into the party's traditional support base.
At an outdoor clothes market in the western Paris suburb of Neuilly-sur-Seine, a bastion of the right, 53-year-old teacher Florence Calder told AFP she was pleased to discover that Macron's policies were "more right-wing than left-wing".
Calder supported Fillon for president but says that if Macron "continues on current form", she would vote for him in 2022 when presidential elections are due.
"Only fools never change their minds," she said.
Wauquiez, who goes up against small town mayor Florence Portelli and a Brittany lawmaker Mael de Calan in Sunday's first round of voting for leader, has pledged to work for party unity if victorious.
"At a time when our political family is in grave difficulty, we have to stand together," he told a rally last week.
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