Amphiphilic tribasic galactosamines potentiate rifampicin in Gram-negative bacteria at low Mg++/Ca++concentrations

Ayan Mukherjee; Danyel Ramirez; Rajat Arora; Gilbert Arthur; Frank Schweizer

doi:10.1016/j.bmcl.2023.129371

Amphiphilic tribasic galactosamines potentiate rifampicin in Gram-negative bacteria at low Mg⁺⁺/Ca⁺⁺concentrations

Bioorg Med Chem Lett. 2024 Jan 1:97:129371. doi: 10.1016/j.bmcl.2023.129371. Epub 2023 Jun 8.

Authors

Ayan Mukherjee¹, Danyel Ramirez², Rajat Arora³, Gilbert Arthur⁴, Frank Schweizer⁵

Affiliations

¹ Department of Chemistry, University of Manitoba, Winnipeg, MB R3T 2N2, Canada.
² Department of Chemistry, University of Manitoba, Winnipeg, MB R3T 2N2, Canada. Electronic address: ramiredm@myumanitoba.ca.
³ Department of Chemistry, University of Manitoba, Winnipeg, MB R3T 2N2, Canada. Electronic address: arorar5@myumanitoba.ca.
⁴ Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB R3E 0J9, Canada. Electronic address: Gilbert.Arthur@umanitoba.ca.
⁵ Department of Chemistry, University of Manitoba, Winnipeg, MB R3T 2N2, Canada; Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB R3E 0J9 Canada. Electronic address: Frank.Schweizer@umanitoba.ca.

PMID: 37301521
DOI: 10.1016/j.bmcl.2023.129371

Abstract

Many antibiotics specific to Gram-positive bacteria like rifampicin (RIF) are inactive in Gram-negative bacteria because of outer membrane (OM) impermeability. Enhancing the OM permeability of these antibiotics with the help of OM perturbants is a promising strategy to develop new agents against Gram-negative bacteria. Here we report the synthesis and biological properties of amphiphilic tribasic galactosamines as potential RIF potentiators. Our results demonstrate that tribasic galactose-based amphiphiles potentiate RIF in multidrug-resistant Acinetobacter baumannii and Escherichia coli but not Pseudomonas aeruginosa in low salt-containing media. Under these conditions, lead compounds 20, 22 and 35 lowered the minimum inhibitory concentration of RIF by 64- to 256-fold against Gram-negative bacteria. However, the RIF-potentiating effect was reduced when bivalent Mg⁺⁺ or Ca⁺⁺ ions were added in the media at physiological concentrations. Overall, our results indicate that amphiphilic tribasic galactosamine-based compounds show reduced RIF-potentiating effects when compared to amphiphilic tobramycin antibiotics at physiological salt concentrations.

Keywords: Aminoglycoside; Antibiotic potentiator; Gram-negative bacteria; Rifampicin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-Bacterial Agents* / pharmacology
Cell Membrane Permeability
Gram-Negative Bacteria
Microbial Sensitivity Tests
Rifampin* / pharmacology
Tobramycin / pharmacology

Substances

Rifampin
Anti-Bacterial Agents
Tobramycin