I am reading about sulfonamides and I see that Sulfamethoxazole is considered to be bacteriostatic on its own, but when combined with Trimethoprim, the combination is considered bactericidal, and I am wondering why is that, because these two antibiotics work on two sequential stages of the enzymatic process of producing folate from para-aminobenzoic acid: From PABA to purines

And this inhibition is bacteriostatic, because it does not kill the bacteria off directly, but simply prevents them from multiplying (which indirectly leads to their demise).

If the antibacterial effect of each antibiotic separately is essentially the same (inhibiting folate production) and the difference is merely the stage, then why is inhibiting two enzymatic stages of the same process confer bactericidal properties? Shouldn't the end result (lack of folate) be just the same? What is it about the combined effect that makes it bactericidal?

I found the same question on Quora, but the answer given there did nothing to actually explain the reason for this shift from bacteriostatic to bactericidal.

Also, the (very) comprehensive antimicrobial manual - Mandell, Douglas, and Bennett’s Principles and Practice of INFECTIOUS DISEASES, Eighth Edition, 2015, chapter 33 - says the following about these antibiotics (bolding is mine for clarity):


The sulfonamides are bacteriostatic in that they inhibit bacterial growth by interfering with microbial folic acid synthesis. More specifically, sulfonamides inhibit competitively the incorporation of PABA into tetrahydropteroic acid, and they may be incorporated into dihydropteroate.


Trimethoprim owes its activity to powerful inhibition of bacterial dihydrofolate reductase, which is the enzyme step after the step in folic acid synthesis blocked by sulfonamides. Trimethoprim is 50,000 to 100,000 times more active against bacterial dihydrofolate reductase than against the human enzyme. Trimethoprim interferes with the conversion of dihydrofolate to tetrahydrofolate, the precursor of folinic acid and ultimately of purine and DNA synthesis (Fig. 33-3). The sequential blockage of the same biosynthetic pathway by sulfonamides and trimethoprim results in a high degree of synergistic activity against a wide spectrum of microorganisms.

Sulfamethoxazole + Trimethoprim:

Potentiation of the action of trimethoprim is seen in combination with sulfamethoxazole ... Variable bactericidal effects have been noted when enterococci are tested against TMP-SMX, but TMP-SMX is not clinically useful.

These excerpts also do not fully explain the mechanism of bacteriostatic effect turning bactericidal.

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