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I had something like that happen. I had to rewrite the whole story on the fly and kept hinting at the big, important mystery that they missed out because they killed the people necessary for the initial hook of the quest.
Punish murderhoboing severely. Party gets wiped and it won’t be fun.
The point of murderhoboing is to create chaos. Don’t give them what they want, just forbid murderhoboing entirely. If there is a non-murderhobo in the party, that person doesn’t deserve to get wiped and if the party is all murderhobos, you should find a different party.