I always felt the Nazis back in TLC felt repetitive and especially so soon after TOD, which showed Indy doesn't always need Nazis to work. I'd like a more out of the box type enemy for 5.
What if...*
1) An older Indy is hired by a wealthy benefactor / ex-pat living in Rio, to travel with an expedition, as a consultant. It turns out that the benefactor is a war criminal that escaped the war crimes trials, and is living in South America. (I have a few problems with my own idea here; namely, that's Donovan-esque, and KOTCS alreadt visited Meso/South America.)
2) Indy is leading a group of his students on a field study in the Himalayas. The sister school of Marshall (or Barnett) is a school in Shanghai. They've sent one of their professors, with a group of his students, to accompany Dr. Jones' party. Upon reaching some location, one of the students from Indy's class goes missing. Indy and the other professor go into a cave to look for the person. They discover a path leading to Shangri-La... Also, was it obvious that the Shanghai professor is, of course, an adult Short Round played by the now age appropriate Jonathan Ke Quan. You get Indy, Shorty, and some new, younger blood into the mix. Bonus points if the inhabitants of Shangri-La are, instead of the British ex-pats in the Lost Horizon version, the NAZIS! lol. Just kidding. I think the villain here could be more of a Mola Ram-type of spiritual boogeyman (or woman).
3) Indy goes looking for the Fountain of Youth. At the end, he falls in. The audience is left to believe he drowned. Out walks Chris Pratt/Bradley Cooper/etc.
*These are all tongue-in-cheek. Please keep that in mind while reading.