Also, I know Klingons are probably fairly tight allies and Romulans are off the table as a big threat right now, but does Starfleet have an important neighboring enemy?
While I had no hope that the
Destiny trilogy itself would be used for story material -- although I don't think it would have prevented Season 2, Seasons 1 and 3 would need a bit more finessing -- the astropolitical changes wrought in its aftermath were just too good to not have through other means, in my opinion.
In a nutshell, the alliances between multi-stellar states become bigger and more entangling. The Khitomer Accords mentioned above are expanded to include the Cardassian Union and the Ferengi Alliance. This is in part a response to a group of formerly isolationist states -- the Breen Confederacy, the Gorn Hegemony, the Romulan Star Empire, the Tholian Assembly, and the Tzenkethi Coalition -- forming a unified currency zone, signing mutual defence assurances, and sharing cloaking technology in what becomes known as the Typhon Pact.
The Pact is not a uniform body -- the Gorn and Romulans pursue back-channel diplomacy with the UFP prior to Hobus, while the Tholians push to destabilize the peace and the Tzenkethi manipulate their allies to varying degrees. The Breen primarily look for technological advantages against a Federation they view as the threat of a counterexample to how they handle a multi-species polity. (Which is why I thought they would have made great cutouts for the Zhat Vash....)
Anyway, since 2009 I've been wanting to see how the Typhon Pact handled the Hobus Event....