The parallel to William Faulkner's 'Southern Gothic' works was explicated in episode 1 of this podcast. Still, I think it would have been unavoidable even without the references to his short story 'A Rose For Emily'.
S Town is short for Shit Town, Alabama, which is the name given by the main person (I can't really call him a character since he's not fictional, can I?) to his home town.
Talking about this show without spoiling the plot is a near-impossibility, so I'll just mention that it starts with an email from the main person to the journalist, asking him to investigate a murder. (It then moves on in a c-o-m-p-l-e-t-e-l-y different direction...)
The decay and dual nature of the South is at the core of the whole documentary, just as the case with Faulkner's writing. The same goes for the obsession with time - its passing and non passing - and clocks.
I did enjoy this! Fortunately there were only seven episodes because addictive podcasts are a lot more consuming than TV-shows. (You can communicate while watching TV but it's much harder to talk with earplugs.)
Still - here comes the caveat! - I didn't enjoy it quite as much as I loved the first 'Serial'.