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The Argentine striker received a retrospective three-game ban from the Football Association (FA) for throwing an elbow at West Ham United’s Winston Reid in City’s last outing, part of the reason why Manchester United are odds on favourites for the game.
His absence is a big blow to a side that have won their three Premier League games so far, but Guardiola has options at his disposal thanks to the great depth in the squad.
Here is a look at three four of the players who could lead the line at Old Trafford on Saturday.
Rejuvenated under Guardiola, Raheem Sterling has been City’s standout performer so far, both domestically and in the Champions League as City qualified for the group stage.
Sterling was always going to be subject to great scrutiny following his £49 million move from Liverpool last summer, and despite scoring 11 goals in 47 appearances in his first campaign at The Etihad, the 21-year-old underperformed for the most part.
A terrible EURO 2016 showing provided further ammunition for the naysayers but things look to be turning around, with Sterling scoring twice in his three Premier League outings so far.
He also drew the penalty from which Sergio Aguero opened the scoring against Sunderland in the first round of matches, just one example of him terrorising opposition full backs.
Sterling was used as a central striker in his Liverpool days with mixed results but could still be an option as part of Guardiola’s fluid forward line.
Nigerian international Kelechi Iheanacho was one of the highlights of what ultimately a disappointing 2015/16 season for Manchester City.
The 19-year-old scored 14 goals in 35 goals in all competitions and his average of a goal every 93.9 minutes was the best in the Premier League.
His form was so good that big money signing Wilfried Bony couldn’t get a regular run in the team, and Iheanacho was rewarded with a new contract last month that will keep him at the club until at least 2021.
A pacy left footer, Iheanacho is a very intelligent player who links well with runners from deep, and he would no doubt be eager to stake a claim for a regular spot in the starting line up.
A somewhat surprising pick up by Guardiola, Nolito signed for the club from La Liga side Celta Vigo for £13.8 million on July 1.
However, the 29-year-old was well known to the City manager having been a key component of the Barcelona B team between 2008 and 2011.
Nolito went on to make five league and cup appearances for the first team but rejected a deal to stay at the Camp Nou and instead headed for Portuguese giants Benfica where he spent two seasons.
After a brief spell Granada, Nolito made the switch to Celta where he established himself as a better than one goal every three games goalscorer.
Since making his debut for Spain in 2014, Nolito has won 14 caps and was a starter during the recent European Championships.
Yet to play for City having joined from Schalke 04 for an initial £37 million, Sane could be the Guardiola’s wildcard if he fancies springing a surprise at Old Trafford.
The 20-year-old shot to prominence back in March 2015 when he scored against Real Madrid at the Santiago Bernabeu and is unlikely to be phased at the prospect of taking on Manchester United.
I joined Manchester City because I believe I can improve as a player, and I also believe that I can be successful and win trophies. To me that is all that matters.
– Leroy Sane
Having made his Bundesliga debut back in 2014, he found the net 11 times in 47 appearances for Schalke and attracted interest from across Europe.
An injury has hindered his progress at City to date but like fellow new boy Ilkay Gundogan, Sane is now ready to go and should at least be among the substitutes.