The mechanism of action of bacimethrin, a naturally occurring thiamin antimetabolite

A Genetic Screen for the Identification of Thiamin Metabolic Genes

“…This suggested the possibility that these proteins might detoxify bacimethrin and CF 3 -HMP by catalyzing hydrolysis of CF 3 -HMP-PP and MeO-TPP, the previously identified toxic forms of the antibiotics (13,16). Synthesis of the necessary substrates to test this hypothesis was carried out as shown in Fig.…”

“…3. Phosphorylations were carried out chemically (21,22) or enzymatically using HMP-P kinase (16,23) or thiamin pyrophosphokinase (13,24,25). HPLC analysis of reaction mixtures containing HMP-PP and either Cof or YmfB showed that both of these enzymes catalyzed the hydrolysis of HMP-PP to HMP-P (Fig.…”

“…This hypothesis was confirmed by demonstrating that YmfB and Cof catalyzed the hydrolysis of MeO-HMP-PP and CF 3 -HMP-PP to give MeO-HMP-P and 4-amino-2-trifluoromethyl-5-hydroxymethylpyrimidine phosphate. This hydrolysis generates resistance to the antibiotics by reducing the formation of their toxic forms, MeO-TPP and CF 3 -HMP-PP (13,16). Cof and YmfB selectively hydrolyze MeO-HMP-PP over HMP-PP with selectivities of 2.8 and 4.5, respectively, and Cof and YmfB hydrolyze CF 3 -HMP-PP over HMP-PP with selectivities of 2.2 and 2.3, respectively.…”

“…1), both of which inhibit E. coli cell growth with a minimum inhibitory concentration (MIC) in the low micromolar range. A recent study demonstrated that the thiamin biosynthetic enzymes convert bacimethrin to 2Ј-methoxythiamin pyrophosphate (MeO-TPP), which inhibits thiamin-utilizing enzymes (13). In the presence of low levels of exogenous thiamin, cell growth is not inhibited by bacimethrin (14,15).…”

Synthesis, antimicrobial activity and molecular modeling study of some new pyrimidine derivatives

“…Furthermore, some pyrimidines were used as hypnotic drugs [22], in addition to their activity as calcium-sensing receptor antagonists [23] and as antagonists of the human A2A adenosine receptor [24] as well. Bacimethrin (4-amino-5-(hydroxymethyl)-2-methoxy pyrimidine) (1) is a pyrimidine antibiotic which is active against several staphylococcal bacteria ( Figure 1) [25,26]. On the other hand, methoprim, 5-(3,4,5-trimethoxybenzyl) pyrimidine-2,4-diamine [27,28] is used, in combination with sulfamethoxazole, as a bacteriostatic antibiotic (trimoxazole) for the treatment of urinary tract infections and Pneumocystis jirovecii pneumonia [29].…”