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The leaders snatched a 2-0 lead within 17 minutes but let their advantage slip before half-time amid a plethora of missed chances - before full-back Scott Galloway proved the hero with a masterful winner in the 73rd minute.
City opened the scoring after 14 minutes when Craig Noone slid a clever through-ball to an unchecked Connor Metcalfe, who ripped a delightful first-time strike home from a tight angle.
Three minutes later, Metcalfe released Scott Jamieson, whose squaring ball was turned into the net by Brisbane s Kai Trewin.
Noone appeared to handball in the lead-up but the goal stood.
Jamie Maclaren had a goal correctly ruled out for a handball in the 27th and, less than a minute later, Brisbane s Joey Champness cut inside and caressed a long-range shot past an outstretched Tom Glover, off the post and into the net.
Five defenders feature in the A-League Team of the Week for Matchweek 19, presented by Bunnings Warehouse.
Melbourne City defeated Newcastle Jets 3-1 in the first game of the Matchweek before three consecutive 0-0 draws took place between Friday and Saturday night.
The Sydney Derby was then to follow, with five goals finding the back of the net in a 3-2 Western Sydney Wanderers win over Sydney FC.
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Melbourne City emerged on top of the A-League table after an eight-game Matchweek 18 came to its conclusion on Wednesday night.
City drew with Macarthur FC on Saturday, April 24. The result sent Patrick Kisnorbo's side one point above both Central Coast Mariners - who took just one point from games against Sydney FC and Brisbane Roar - and the Sky Blues, who drew level with the Mariners after notching four points from two games in Matchweek 18.
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The Roar held sway for long periods at Central Coast Stadium on Wednesday night, Macaulay Gillesphey scoring in the 19th minute and Joey Champness bagging a bellringer in the 56th before late shows to Alex Parsons and Masato Kudo.
It was a night to forget on home turf for the Mariners, who also lost key forward Marco Urena to a 62nd-minute red card for an ugly challenge on Jay O Shea.
Arguably the form team of the competition with three consecutive wins, the Roar are now just a point out of the top six and have a game in hand over most sides.