Amazing how much they struggle ain't it? even someone as technically adept as Floyd has his problems. It's that different look and things coming from the opposite side. When all things are even southpaws have a advantage no doubt. Not only because orthadox fighters are not used to seeing them often (btw i don't know if that's the main reason, there's more southpaws now than ever before and it should be standard to get plenty of sparring with one, back in the day it must've been more difficult because there just wasn't that many around). But i think the main reason orthadox fighters struggle is because the lead hands are so aligned that it makes it very difficult to catch a skillful southpaw with your jab and time him. Most of your punches coming from that angle get easily deflected or slipped.
The thing i don't understand is how orthadox fighters don't use their advantages. They have the same advantages that southpaws have over them. The same problem the orthadox stance sees in facing the southpaw, the southpaw also sees them problems from the opposite side too. But they generally win the foot positioning battle. I think it's just more than orthadox fighters not being used to southpaws, although that's got a lot to do with it. It must be weird when you've been told and trained to expect punches from one angle and direction and they keep coming from the opposite. I'm a southpaw myself and when i was in the gym i always found that i had an advantage. Even guys that were MUCH better than me would occassionally get caught with BS punches by me. And it was easier to slip their over the top punches and get under then it was against another southpaws. Most of time i would always end up almost behind them if i somehow made them even partially miss we would be get into a tangle.
The key as you say Mand. is trying to win the foot positioning. Keeping the lead foot outside the southpaws lead right foot and moving away from the power hand. The problem is the orthadox fighter has to keep thinking about doing these things and as you know Mand when i fighter has to THINK and not be instinctive it's not ganna work and he's ganna start hesitating and not getting off. I have seen fighters trying to think against southpaws and it only takes that milli-second while you're thinking and BOOM! You could actually see USS Cunningham doing this on saturday in patches. In his expressions and mannerisms you could see he was thinking 'must do that, must remember to do this'.
I think the worst must be to fight a technically good counter punching southpaw. If the southpaw takes a step back, tucks his chin and draws the orthadox fighters lead and gets him to come then the orthadox fighter is so open to be countered inside his lead. This is probabily the move and punch that i've seen southpaws hurt orthadox fighters most with. Incidently, it was the same one that Cunningham got caught with a few times and the one that dropped him (IIRC) was a perfect illustration of it.
One of the best guys who knew how to fight southpaws was Mike Spinks. His body rhythm allowed him to offset people. He also threw one of the best punches to hurt a southpaw with and that's a sneaky left hybrid uppercut. Southpaws really struggle against this punch. I've seen it over and over. Spinks actually ko'd Marvin Johnson a really good southpaw with this exact punch.
5.12 of the vid below.
For me the trick is to get southpaws coming forward. In general most of them have an advantage when you show your hand. Keep them coming forward and don't just follow them around for no purpose they love that. Be instinctive is also another way to offset a southpaw.
In todays era Bernard Hopkins probabily fights southpaws the best. He does exactly what they're aiming to do to him and he flips the switch. He draws their lead and brings them into no mans land. He's also very instinctive and throws his punches, especially the straight right (the best punch against a southpaw) with quick release and accuracy. His experience of training with guys like John David Jackson also helps him and of course his all round technical ability and awareness. Something most orthadox fighters don't have.