Effect of d-serine on the antibiotic inhibition of one-carbon metabolism

Abstract

On minimal medium, growth of Escherichia coli K-12 dsdA mutants, lacking the inducible enzyme D-serine deaminase, is permanently inhibited by D-serine at concentrations higher than 25 ~tg/ml [1]. In this system, D-serine interferes with L-serine metabolism, showing a severe inhibition of 3phosphoglyceric acid dehydrogenase, the first enzyme of the L-serine biosynthetic pathway, and of pantothenate biosynthesis, preventing the coupling of fl-alanine to pantoic acid [2]. L-Serine is a major Source of methyl groups, and the transfer of these groups is made via tetrahydrofolate (THF), of which p-aminobenzoic acid (PABA) is a structural component. It is well known that sulfonamides and-trimethoprim inhibit T H F metabolism. On the other hand, microcin 15m inhibits homoserine transsuccinylase, the first specific enzyme of the methionine pathway, acting as a 'false end-product' 3]. This inhibition stops methionine synthesis, and ence the flow O f one-carbon fragments via Sadenosylmethionine is reduced. Therefore, it was interesting to know whether a n inhibition of both one-carbon fragment metabolic pathways by D-serine, and several other bacterial inhibitors, could produce inhibitory effects greater than the sum of their individual effects. In the strain E. coli 405, we have observed that D-serine inhibits growth in liquid and solid medium only at concentrations much higher than those described for dsdA mutants. In this paper it is shown that D-serine, at concentrations subinhibitory for the strain E. coli 405, greatly enhances the antibiotic effect of sulfonamides, trimethoprim, microcin 15m, and methionine analogs on this strain.