Luciferase

For me, Tirek, Chrysalis and Cozy Glow. In just the one season they worked together, they managed to pretty quickly and efficiently destabilize Equestria to the point of reverting back to it's pre-founding days, right down to the windigos and threat of eternal winter. Had they been a united force way sooner, they likely could've done even more lasting damage since they knew how to especially hit Ponykind right in its weak-points. Special mention goes to Discord. With how easily he just toys with the very fabric of reality like it was nothing, Discord, in theory, could do some serious damage if he so wanted or if things got to a certain point. Of course though, that's veering away from canon, since the Discord we got is more of a trickster out to entertain himself versus a literal walking force of destruction, though had FiM not ultimately been a TV-Y show and things were allowed to be more serious, I can imagine Discord having the potential to be a much larger, more dangerous threat