Paraphrasing Rocky, "Southpaws should be illegal!" Fighting a bout with a mismatched lead can be tricky- the angles and counters are different, and depending on where you train, finding a good southpaw fighter may be difficult. (Maybe go raid a JKD school? After all, Bruce Lee did love to advocate strong side forward fighting to use the lead straight blast)
Joe Lauzon appears in this MMA Boxing instructional on how to defend and counter against a Southpaw. I rewrote the general gist so that it goes both ways.
-Stay outside the lead leg (aka staying away from the power side)
-Make them move
-Shoot in for the takedown off his jab
-Defend against their cross (Don't turn away, counter with own cross)
-Defend against the lead hook and counter with cross
-Shoot off your lead hook