My partner's a microbiologist, and one thing that I've come to realize is that the microbial world isn't really much like a shrunken-down version of macroscopic ocean life. There are a lot of "free-swimmers", but many microbes aren't, and the ones that aren't are pretty interesting too.
Like if you consider microbes that live in and produce biofilms... if you make it a story about the survival of any individual, their behavior doesn't make much sense. Once you have a high enough population density, they send a special signal to each other, and 99.99% of them explode into a slime of biopolymers. That slime is the medium on which the next generations -- the descendents of the 0.01% -- grow, until those descendents too reach the required density. "Suicide signals" like this don't make sense from an individual survival perspective; if evolution worked like that, these signals wouldn't exist because the advantage would be to any population that mutated such that they no longer responded to these signals. It does make sense, however, from the perspective of the colony -- or even the perspective of the biofilm. (You can, if you want, treat a biofilm as an "organism" consisting of a disorganized mass of extracellular biopolymers that maintains itself, grows, and reproduces by cultivating a population of constantly growing and exploding bacteria.)
Also, microbes differ in the extent to which they have a genome more like humans -- full of lots of special-purpose "code" that can be environmentally turned on and off -- vs. a more minimalist genone where this sort of environmental adaptation is accomplished by mutation itself. These more minimalist organisms underscore that mutation isn't about navigating an upward path vs. misguided (and often fatal) mistaken mutations; organisms can mutate back and forth as a regular part of their lifecycle. (Well, not their individual lifecycle, but when a generation only takes a few minutes, this kind of environmental adaptation is entirely reasonable.)
Anyway, this is a neat part of being a microorganism that's not really well captured in games where you could reskin the characters as fish and the gameplay would be basically the same. That, and from the point of view of the tinier microorganisms, it's not like empty space; their world has terrain, which is good from a gameplay standpoint.
I'm thinking a system almost like Crusader Kings II would be the right way to go, where individual death is frequent and treated as a part of progress rather than a failure. Your goals as a player might be stymied by a death or they might be furthered.
