Synthesis of inhibitors of bacterial cell wall biogenesis. Analogs of D-alanyl-D-alanine

Goyer

Antimicrob Agents Chemother

1977

Position 4 analogues of r-alanine in the peptide subunit of uridine 5'-diphosphate-N-acetylmuramyl-Alal-DGlu2-Lys3-DAla4-DAla5 have a significant inhibitory effect on penicillin-sensitive peptidoglycan synthesis in Gaffkya homari (C. V. Carpenter, S. Goyer, and F. C. Neuhaus, 1976). The specificity profile of this in vitro system has been used as a basis for designing analogues with potential antibacterial activity. To circumvent the specificity determinants exerted by Dalanine:D-alanine ligase (adenosine 5'-diphosphate), attention was directed to DD-dipeptides of the type z)-alanyl-analogue-i-alanine as a method for incorporating analogues into position 4 of the peptide subunit in vivo. Of the three dipeptides, DAbu-DAla, DNva-DAla, and DVal-DAla, only DNva-DAla (5 x 10-4 M) inhibited the growth of Escherichia coli W in the presence of 5 x 10-6 M Dcycloserine. This concentration of D-cycloserine did not inhibit growth, but it potentiated the bactericidal activity of the dipeptide. The lack of antibacterial activity observed with DAbu-DAla and DVal-DAla was correlated with the poor ability of these dipeptides to be taken up via the dipeptide transport system of this organism. Prevention of lysis induced by DNva-DAla plus D-cycloserine by certain dipeptides and not by others supported this correlation. It is proposed that the r)-norvalyl residue of the dipeptide is incorporated in vivo into position 4 of the peptide subunit of peptidoglycan, and that this subunit is not an effective substrate in the reaction(s) catalyzed by the penicillin-susceptible enzyme(s) of cross-linked peptidoglycan synthesis.

“…Analogues of DAla-DAla with C-terminal substituents have been synthesized and tested for antibacterial activity (3,15). None of these compounds showed significant antibacterial activity.…”

Section: Discussionmentioning

confidence: 99%

Growth Inhibition of Escherichia coli W by d -Norvalyl- d -Alanine: an Analogue of d -Alanine in Position 4 of the Peptide Subunit of Peptidoglycan

Goyer

Antimicrob Agents Chemother

1977

“…Data collection: APEX2 (Bruker, 2005); cell refinement: SAINT (Bruker, 2005); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: PLATON (Spek, 2009) and ORTEP-3 for Windows (Farrugia, 1997); software used to prepare material for publication: publCIF (Westrip, 2010). Tetrazoles derivatives are an important class of compounds, which can be used in the fields of bioorganic and medicinal chemistry as antibacterials, anti-cancer, heart disease, neurodegenerative disease, and antifungal activity (Smissman et al,1976;McGuire et al, 1990;Lunn et al, 1992;Itoh et al, 1995;Upadhayaya et al, 2004;Wu et al, 2008;Rostom et al, 2009. The tetrazole moiety has long been established as a bioisostere of a carboxyl unit (Burger, 1991). A major advantage of tetrazoles over carboxylic acids is that they are resistant to many biological metabolic degradation pathways (Singh et al, 1980).…”

Section: Methodsmentioning

confidence: 99%

“…For the biological activity and medicinal properties of tetrazole derivatives, see : Smissman et al (1976); McGuire et al (1990); Lunn et al (1992); Itoh et al (1995); Upadhayaya et al (2004); Wu et al (2008); Rostom et al (2009);Burger (1991); Singh et al (1980). For the synthetic procedure, see: Adams & Langley (1941a,b).…”

Section: Related Literaturementioning

confidence: 99%

N-(Cyanomethyl)benzamide

et al. 2010

Key indicators: single-crystal X-ray study; T = 296 K, P = 0.0 kPa; mean (C-C) = 0.002 Å; R factor = 0.038; wR factor = 0.109; data-to-parameter ratio = 13.6.In the structure of the title compound, C 9 H 8 N 2 O, the amide group is twisted by a dihedral angle of 21.86 (7) with respect to the benzene ring, while the planes of the benzene ring and cyanomethyl group form a dihedral angle of 53.13 (11) . In the crystal structure, molecules are linked via N-HÁ Á ÁO hydrogen bonds, forming a chain running parallel to the a axis. Related literature ExperimentalCrystal data Data collectionBruker X8 APEXII CCD areadetector diffractometer 11132 measured reflections 1920 independent reflections 1433 reflections with I > 2 (I) R int = 0.027

“…In this previous work they were reported to be inactive, which contrasts starkly with the data we report below. However, these differences in results may be attributed to differences in the culture medium that was used, such as peptone content, the specific bacterial strains studied or even differences in the inoculum [18,19]. Our more extensive investigation focused upon clinically relevant strains of pathogenic bacteria, and used protocols that have now been established as clinical standard over many years.…”

Section: Microbiological Evaluationmentioning

confidence: 99%

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

et al. 2020

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.