Frequency and mechanism of resistance to antibacterial action of ZM 240401, (6S)-6-fluoro-shikimic acid

Abstract

Spontaneous resistance to (6S)-6-fluoro-shikimic acid arose in Escherichia coli and other enterobacteria at high frequencies, between 10 ؊5 and 10 ؊4. Two resistant variants of E. coli were tested for their susceptibilities to the diastereomeric compound, (6R)-6-fluoro-shikimate, and both of them had become resistant to this compound as well. (6S)-6-Fluoro-shikimate-resistant variants of E. coli generally failed to transport [ 14 C]shikimate. In E. coli K-12, (6S)-6-fluoro-shikimate resistance cotransduced with his at the same frequency as shiA, a gene locus that governs shikimate transport phenotypes. We propose that the loss of susceptibility to (6S)-6-fluoro-shikimic acid in spontaneous resistant variants is due to the loss of activity of the transport system by which it enters the bacterial cytoplasm. Sutherland et al. (23) synthesized the (6S)-6-fluoro derivative of shikimic acid (Fig.

Escherichia coli chorismate synthase

“…This is because this substrate analogue is turned over [26], as discussed above, and the susceptibility of E. coli to the antimicrobial agent (6S)-6-fluoroshikimate is overcome by the addition of 4-aminobenzoate, a folate co-factor precursor, and not by the aromatic amino acids phenylalanine, tyrosine and tryptophan [34]. Spontaneous resistance to this antimicrobial agent appears to be due to the loss of activity of the transport system by which it enters the bacterial cytoplasm [36]. Since (6R)-6-fluoro-EPSP (Figure 3b) lacks the (6proR)hydrogen, it is, as discussed above, not a substrate of chorismate synthase [14].…”

Characterization of Streptococcus pneumoniae 5‐enolpyruvylshikimate 3‐phosphate synthase and its activation by univalent cations

“…The shikimate pathway synthesizes aromatic amino acids, p ‐aminobenzoic acid and other essential metabolites such as ubiquinone, menaquinone and vitamin K. Bacteria, like plants and fungi, require a functional chorismate pathway to survive, and, as the shikimate pathway has not been identified in vertebrates, this pathway is an attractive possible source of antibacterial targets [1]. The potential of enzymes in this pathway as antibacterial targets has recently been illustrated by a series of shikimate derivatives that possess antibacterial activity via interaction with enzymes in this pathway [2,3]. Moreover, the indispensability of this pathway for bacterial survival has been illustrated by the observation that bacterial mutants lacking 5‐enolpyruvylshikimate 3‐phosphate (EPSP) synthase, a key enzyme in the pathway, are unable to survive and cause infection in animal models [4,5].…”

The 2.3-Å Crystal Structure of the Shikimate 5-Dehydrogenase Orthologue YdiB from Escherichia coli Suggests a Novel Catalytic Environment for an NAD-dependent Dehydrogenase

“…The shikimate pathway is essential to bacteria, fungi, plants, and parasites but is not used in mammals (1,2), making the enzymes involved in this pathway attractive targets for the development of broad spectrum antibiotic drugs (3)(4)(5)(6) and herbicides (7). The pathway in Plasmodium, Toxoplasma, Cryptosporidium, and Eimeria parasites has attracted attention recently (1, 2) but also holds promise for the development of drugs to inhibit the growth of fungi and bacteria (8).…”