While it’s a lot more complicated than this, you can get a rough impression of why by just comparing the structure of with saccharin (bi-cyclic “gamma-lactam” with sulfur (as sulfone) at the alpha position) with the original “sulfa drugs” (sulfa = “sulfonamide”) and the penicillin-family antibiotics (bi-cyclic “beta-lactam” with sulfur at the beta position).

Saccharin is both a lactam and a sulfonamide and sulfur-containing lactams and things close in structure to sulfonamides in general tend to inhibit DHPS which doesn’t usually kill bacteria but makes it so they can’t grow or multiply and the numbers will end up shrinking as they expire.

Penicillin was discovered just slightly earlier than the sulfa drugs, but the big advantage of sulfa drugs is that they could be artificially chemically synthesized at quantity and relatively easily even with 1930s tech. While it’s technically possible to do a total synthesis of penicillin, it’s completely impractical compared to just having brewing giants vats of microorganisms making it for us, which is how it’s done to this day.

Interestingly, a common nexus between saccharin and these effects is the gut microbiome, pointing at a direct effect of this sweetener on bacteria (Suez et al, 2014; Bian et al, 2017; Skurk et al, 2023; Del Pozo et al, 2022). Nevertheless, despite the unequivocal evidence of the impact of saccharin on the microbiome, its direct effect on the bacterial physiology and its underlying mechanism remains unexplored.

It’s interesting to have another example of antibiotic resistance / biofilms, though.

I’ve wondered if biofilms, quorum sensing, and other complex microbial community dynamics — which are critical to their survival in difficult environments like hospitals — are the reason antibiotic resistance doesn’t become universal; perhaps antibiotics exist because they primarily damage or are involved in the community dynamics, and so bacteria are put on the horns of a dilemma if they try to become resistant to every antibiotic.