Assessment of the rules related to gaining activity against Gram-negative bacteria

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 Delta tolC, D22, Delta 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.

Automated summary

By repositioning an antimalarial compound class and derivatising it based on the eNTRy rules, no substantial improvement was observed against E. coli wild-type K12, but distinct activity differences were seen in mutant strains. The study highlighted that the rules for enhanced activity against Gram-negative bacteria may not always be applicable, with glycine derivatives showing the highest antibacterial activity despite efflux issues.