It's actually quite easy to handle the classic trope of encountering 'opponents of increasing toughness' in this genre, though you don't have to be ultra-predictable.
With the assumption that you and your adventuring party have come into possession of one of more of these cursedly powerful weapons, there is one binding core motivation of your human (and near-human) opponents: they want the guns (or whatever form these weapons have taken in your campaign).
These are the hired help, who are tasked with killing the current keepers of the weapons. They're capable of wielding weaponry, but aren't necessarily that skilled, cunning, or courageous. And they tend to get mowed down quite a bit by the PCs.
These are professionals who serve the big boss (or one of his lieutenants). They are considered exceptional in some way, and perhaps have some renown in one particular skill or in a particular area.
However these guys -- while capable and reliable -- can still get killed. They're also nowhere near as dangerous as the higher-ups in the food chain. They're most dangerous as canny and cautious, and very skilled at finding out information that is passed on to their masters.
You can consider these jokers to play in the range of power level between the Hired Guns and the Lieutenants. Normally loners, but possessed of a unique set of skills, they are placed in the adventure to act as foils to the PCs. They can help or hinder them, and may in fact do both because they are after the guns not because they want them for themselves, but because they wish to profit from the acquisition (either by selling the guns or trading them with others for favors).
Needless to say, they tend to meet their just rewards if they ultimately choose the less virtuous path.
These are the right-hand men (and women) of the big boss. They have special abilities that set them apart from most mortals, such as being tougher and capable of dealing greater damage to opponents.
They may still have some character flaws, but are seldom struck by outright cowardice -- and even if they are, they are tempted to stay or hide and double-back when fortunes favor them due to a streak of pure malice.
The Big Boss
Driven, Fearless, Powerful, Cunning, and Charismatic. That's the big boss. Capable of holding and commanding the loyalty of a small band of villains and cutthroats of consummate skill in his thrall, and possessed of big plans for the guns and the rewards that they promise.
Taking him down is never easy -- and he never seems to stay down forever.
Worse than that, if any of his lieutenants escape, they tend to have ways of bringing this nasty piece of work back from the dead! And if that isn't an option, sometimes the dark patrons who granted him is powers aren't happy with the incomplete nature of his work -- and send him back more or less the same personality-wise, but usually a whole lot more dangerous and with a lot more power and resources at his beck and call.