C-Terminal 1-Aminoethyltetrazole-Containing Oligopeptides as Novel Alanine Racemase Inhibitors

Abstract

In clinical culture media inoculated with patient samples, selective inhibition of commensal bacteria is essential for accurate diagnosis and effective treatment, as they can mask the presence of pathogenic bacteria. The alanine analogue, 1-aminoethyltetrazole was investigated as a potential alanine racemase inhibitor. For effective uptake and enhanced and selective antibacterial activity, a library of C-terminal 1-aminoethyltetrazole containing di- and oligopeptides were synthesized by solid phase peptide coupling techniques. The investigation of the antimicrobial activity of the synthesised compounds identified several clinically applicable selective inhibitors. These enabled differentiation between the closely related bacteria, Salmonella and Escherichia coli, which can be difficult to discriminate between in a clinical setting. In addition, differentiation between enterococci and other Gram-positive cocci was also seen.

Phosphonopeptides Revisited, in an Era of Increasing Antimicrobial Resistance

“…In the period subsequent to the work disclosed within this paper we performed systematic modifications to the structures of the inhibitors with this other goal in mind. The results of these subsequent investigations form the basis of our second and third papers which may be found within this Special Issue of molecules dedicated to microbial detection and identification [27,28].…”

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“…C-terminal 1-aminoethyltetrazole containing di and oligopeptides synthesized by solid phase peptide coupling technique were identified as novel and potential alanine racemase inhibitors 29 .…”

Racemases and epimerases operating through a 1,1-proton transfer mechanism: reactivity, mechanism and inhibition

“…Indeed, fosfalin 101 is delivered to bacterial cells as a ''dipeptide'' alafosfalin 102. 231,236 Therefore, a series of di-and tripeptide derivatives were synthesised and tested. 236 The SS-Ala-Ala analogue 103a was active against several Gram-negative species, whilst the SS-norvalene-AET 103b, SS-Leu-AET 103c and SS-Phe-AET 103d analogues were active against several Gram-positive species.…”

“… 236 The tetrazole group is a well-established bioisostere of the carboxylate group, 236 and hence 5-(1-aminoethyl)tetrazole 100 should behave as an analogue of alanine. S - and R -5-(1-aminoethyl)tetrazole 100 (AET) were inactive when tested against a series of Gram-negative and -positive bacteria 236 but this is unsurprising as it is known that alanine is imported into bacterial cells as an oligopeptide. Indeed, fosfalin 101 is delivered to bacterial cells as a “dipeptide” alafosfalin 102 .…”

“…Therefore, a series of di- and tripeptide derivatives were synthesised and tested. 236 The SS -Ala-Ala analogue 103a was active against several Gram-negative species, whilst the SS -norvalene-AET 103b , SS -Leu-AET 103c and SS -Phe-AET 103d analogues were active against several Gram-positive species. The SSS -Ala-Ala-AET analogue 104 showed similar activity to 103a .…”