I really am starting to like the 'Neptune Bad' theory - maybe he won't be the big bad in terms of 'one fought', but in terms of 'morally evil' - i.e. Spandam is really the main antagonist of Enies Lobby, behind all the plotting, ongoing symbol of the Ohara Buster Call, Lucci's primarily his psychotic bodyguard.
Straw Hats fighting New Fishmen is gonna happen since that many 'Box-Intros' of names on a posse of strong-looking guys is a clear 'henchmen! to be beaten!' sign. I really like the idea, though, that they end up reconciling or seeing the Fishmen's point of view, even showing them that humans aren't all bad.
I'm currently…well, hoping (theorizing a little) that Van Dekken's some kinda resistance fighter, or at least complicated, and that Neptune is authoritarian as anything and/or co-opted by the drug suppliers. A scenario where the villain mob to be beaten undergoes a Franky Family-style moral side-change would be wicked fun. AND avoid all the well-pointed-out "Boo, Arlong Pirates w. drugs YAWN" possibilities inherent in the concept as currently laid out.
I think that it's way too early to meet Big Mom; sure she's not likely to be the strongest of the Yonkou (with Shanks around) but it's down to her, Kaidou, Shanks, Blackbeard, Sengoku/Garp(?) and the Admirals as far as the known A+-listers go.
IF we meet her it's likely to be a modified Mihawk intro - lots of
Luffy: "Wow, granny, you're super strong!"
Nami/Usopp: "STOP OFFENDING HER!"
Big Mom: "Kekeke...still standing after that? That red-haired idiot wasn't wrong about you..." etc. (standard Shonen 'one-day-but-not-yet' stuff.)