According to KenV (who seems to have abandoned this forum), a big concern with one engine per pylon was it messing up the ability to load/drop munitions from the wings.
Back around the year 2000 I was on a team that was looking at just that - replacing each two engine pod with a single PW2000 or RB211-535 (e.g. 757 engines). The potential improvements were massive - the increased thrust and better fuel burn meant greatly increased range, payload, and massive fuel costs savings. Just the savings in fuel made it look like a no-brainer with the reduced fuel burn paying for the costs of the re-engine.
Allegedly the USAF nixed it because they feared making the BUFF more capable would hurt their case for buying more B-2s (which of course didn't happen).