Open AccessAssessment of the rules related to gaining activity against Gram-negative bacteria
Author(s) -
HenniKaroliina Ropponen,
Eleonora Diamanti,
Alexandra Siemens,
Boris Illarionov,
Jörg Haupenthal,
Markus Fischer,
Matthias Rottmann,
Matthias Witschel,
Anna K. H. Hirsch
Publication year - 2021
Publication title -
rsc medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.754
H-Index - 55
ISSN - 2632-8682
DOI - 10.1039/d0md00409j
Subject(s) - gram , escherichia coli , gram negative bacteria , bacteria , mutant , gram positive bacteria , microbiology and biotechnology , biology , chemistry , computational biology , biochemistry , genetics , gene
In the search for new antibacterial compounds, we repositioned an antimalarial compound class by derivatising it based on the so-called "eNTRy" rules for enhanced accumulation into Gram-negative bacteria. We designed, synthesised and evaluated a small library of amino acid modified compounds together with the respective Boc-protected analogues, leading to no substantial improvement in antibacterial activity against Escherichia coli wild-type K12, whereas more distinct activity differences were observed in E. coli mutant strains Δ tolC , D22, Δ acrB and BL21(DE3)omp8. A comparison of the activity results of the E. coli mutants with respect to the known rules related to enhanced activity against Gram-negative bacteria revealed that applicability of the rules is not always ensured. Out of the four amino acids used in this study, glycine derivatives showed highest antibacterial activity, although still suffering from efflux issues.