I can't see the Persians defeating the Macedonian war machine in a pitched battle; as the 'moderate' Athenian politician Aeschines said when rebuking the anti-Macedonian leader Desmothenes for celebrating when Philip II was assassinated as 'ending' the threat of attack on Athens, the only change was that the Macedonian army was minus one man.
If Alexander is merely wounded, the war would be 'on hold' for the duration of his convalescence, and the Macedonians would hang onto Mesopotamia while the Persians rebuild their army behind the barrier of the Persian Gates and (less impenetrable as it has no easily-blocked passes) the Zagros mountains. Darius has lost two major battles and most of his army, plus all his Western provinces , and he was never a skilled campaigner (except in his quick moves in NW Syria ahead of the battle of Issus which may have been suggested by his generals) or noted for his boldness. He offered Alexander a truce and half his empire ahead of Gaugamela, before that crushing defeat made his position precarious; would he have had the nerve to march his Eastern troops into Mesopotamia SW from his base at Ecbatana (modern Hamadan) and tackle the Macedonians if Alexander was merely incapacitated rather than dead, and if his belligerent great nobles like Bessus forced him to do it would they beat an Alexander who was directing his battle from his sickbed in the rear and presumably sending relay messengers to tell his divisional commanders what to do?
The delays to Macedonian reactions in a swift-moving battle might enable the battle to be more equal than if Alexander was commanding 'in the field', but the Persians could probably only win by weight of numbers and after Gaugamela they had less of an advantage in this. (Mazaeus satrap of Babylon had now defected to Macedon with his regional command, which had formed one wing of the Persian army at Gaugamela, and presumably he would be kept a close eye on in any battle to make sure he did not defect back.) The Macedonians retained quicker reflexes in battle, a skilled leadership group of generals used to taking initiatives in command, and more of a 'punch' with their armoured cavalry, plus the spear-bristling infantry 'hedge' of the phalanx; the main threat to them in battle was exhaustion in the heat plus being pushed back by weight of numbers so the Persians' best hope was bringing in Central Asian steppe nomads which would take a year or two to arrange (and how could they pay them after losing so much territory plus the Babylon and Susa treasuries?). Alternatively the bedridden Alexander would appoint the highly competent Parmenion to take his place as overall commander at a battle and leave him to do as he saw fit, or give this role to a contemporary and close aide from the Macedonian nobility, used to taking decisions, like Ptolemy (rumoured to be his half-brother), Hephaistion (military capability unclear but highly trusted),Perdiccas (A's apparent choice as regent for his unborn child when he did die in 323), or Craterus.
If Alexander was dead the only adult Macedonian royal available to be elected King and take nominal command of the army and government was Arrhidaeus, who seems to have been mentally not up to any 'command' role and possibly brain-damaged from babyhood (rumoured to be due to poison by Alexander's ferocious mother Olympias). Alexander was not even married, and his sister Cleopatra was away in Epirus as recently-widowed wife of her uncle King Alexander (k 331 in Italy); A's cousin Amyntas had been murdered at A's accession as a potential rival and had left a small daughter but no son, and the only other distant relatives were the Lyncestid brothers (remote Macedonian royalty) of whom 2 of 3 had already been executed and the third was shortly to be implicated in Parmenion's son Philotas' alleged 'plot'
and killed. If P and his son Philotas tried to get this candidate elected, Alexander's close friends and generals would presumably block it - though Parmenion might then threaten a civil war/ mutiny if he faced arrest. The liklihood is that the Macedonian military elite would temporarily cohere round a nominal candidate as they did in 323, ie Arrhidaeus, and defeat any Persian counter-attack - Ptolemy, Perdiccas and Craterus (and Philotas?) were all competent generals and the army had rehearsed battle-tactics under Philip for many years. But they would not risk an attack through the Persian Gates on Persepolis, and would probably just hold onto what A had conquered so far - with Parmenion, who had wanted A to accept Darius' offer of half the empire earlier, now persuading them to a temporary peace. Arrhidaeus would be married off (to Amyntas' daughter as in OTL?) to provide an heir, but as the Oriental 'fusion', Persian court lifestyle,
and Mesopotamian residence of the new empire were controversial initiatives of Alexander alone this would not occur.
Probably the court would be moved back to Syria to set up a Mediterranean trading city
capital like OTL Antioch, anchored there by the lands and loot acquired by Alexander's ambitious inner elite who were greater figures in the new Eastern empire than they had been in Macedon and could call on garrison troops and local recruits to shore up their new power. The elite had every reason to stay in the Levant and exploit its potential as the new warlords there, not base themselves back in Macedon as 'big fish in a small pond'. Mesopotamia would be an outpost mostly useful for Eastern trade, and the equivalent of the OTL Seleucid and Ptolemaic empires as one state (or breaking up later into more) would be created centred on Syria and Egypt. Alexander would be a 'cult' figure as the centre of dynastic legitimacy and hailed as a semi-divine hero by his former senior commanders, and given their ruthless rivalries it is most likely that any 'figurehead' monarch like Arrhidaeus ('Philip IV') and a son of his would be very lucky not to be pushed aside in a 'War of the Successors' . Logically, Ptolemy - cautious and content to hang onto manageable Egypt in real life - was less likely to gamble on gaining the entire empire by coup or war than Perdiccas, who as in OTL but with more success might try to get hold of A's sister Cleopatra , marry her, and create his own line of royalty. He is the likeliest to hold this smaller than OTL empire together, barring a blocking coup or revolt by his rivals.
As for Darius - in real life he was to be overthrown and killed in 330 after losing Persepolis too, and his ambitious cousin Bessus, satrap of Bactria (basically S and W Uzbekistan/NW Afghanistan) so with his own troops, could depose him if he failed to mount or win a counter-attack in 330-29. Then a 'rump' Achaemenid state survives on the Iranian plateau, minus its W lands and probably reliant on mercenaries from the steppes to survive Macedonian attack so at risk of destabilization and overthrow. The monarchy has now lost most of its central army and richest provinces, so Bessus is unlikely to risk it all on invading the West bar a few morale-raising raids. We then end up with a weaker, Parthian-style state, and either a Macedon/Levant empire (like the early Byzantine state to 602) or a group of feuding military Successor monarchies. Alexander is still a legend, but without the exotic Central Asian/ Indian part of the myths - and without the worst examples for future literary debate of his drinking, wasting his troops' lives (eg in the Gedrosian desert), unrealistic megalomania (eg in marching into India), or murders (eg Philotas Cleitus and Callisthenes).