Structure-activity relationships of potentiators of the antibiotic activity of clarithromycin against Escherichia coli

Gifty Blankson, Ajit K. Parhi, Malvika Kaul, Daniel S. Pilch, Edmond J. LaVoie

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Several studies that have identified agents that potentiate the antimicrobial activity of antibiotics, but there are limited insights into their structure-activity relationships (SAR). The SAR associated with select N-alkylaryl amide derivatives of ornithine was performed to establish those structural features that were associated with potentiation of the antimicrobial activity of clarithromycin against E. coli ATCC 25922. The data indicate that the N-propyl derivative was slightly more active in reducing the effective MIC of clarithromycin against E. coli ATCC 25922. In addition, the S-enantiomer of compound 9 was somewhat more potent than the R-enantiomer in potentiating clarithromycin activity. No significant enhancement in potentiation activity was observed with the conversion of these secondary amides to their N-methyl tertiary amides. Formation of the N-methyl or N,N-dimethyl derivatives of the primary amine of 9 was associated with the loss of potentiation activity. Conversion of this primary amine to a guanidine was also not associated with an increase in potentiation activity. Among the isomeric diamino pentamides, 15 potentiated the antibacterial activity of clarithromycin to the greatest extent. In addition to these amide derivatives, the desoxy derivatives 16 and 18 were the more potent potentiators within this triamine series. The relative location of the primary amines, as indicated by the relative differences in the potentiation observed with 16 compared to 14, appears to be a critical factor in determining potentiation activity. Cell-based membrane permeabilization and efflux inhibition studies in E. coli ATCC 25922 suggest that the potentiation of clarithromycin activity by 16 reflects its ability to inhibit efflux pump activity and to a lesser extent its actions as a permeabilizer of the outer leaflet of the outer cell membrane.

Original languageEnglish (US)
Pages (from-to)30-38
Number of pages9
JournalEuropean Journal of Medicinal Chemistry
Volume178
DOIs
StatePublished - Sep 15 2019

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Keywords

  • Antimicrobial
  • Clarithromycin
  • E. coli
  • Potentiators
  • Synergy

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