When fighting Python, lock on to him with L and shoot him when he becomes visible through the fog. Make sure to continuously back up, otherwise he will lunge forward and knock you down with his weapon. It is also a good idea to plant the TNT with a soldier other than Snake. By doing this, when you begin the fight you will start as the character you planted the bomb with. Then if your character dies, you will have the option of selecting the next player to fight with so that you can save Snake to finish the job after Python has been weakened.

The best weapon to use against Python is the shotgun. It will knock him down and you can shoot him again before he gets back up. Additionally, the shotgun deals a lot of damage but does not require you to do any fancy moves.