Synthesis and Biological Evaluation of Fingolimod Derivatives as Antibacterial Agents

Abstract

We recently identified fingolimod as a potent antibiofilm compound by screening FDA-approved drugs. To study if the antibacterial activity of fingolimod could be further improved and to explore in-depth structure−activity relationships, we synthesized 28 novel fingolimod derivatives and evaluated their efficacy against Staphylococcus aureus grown in planktonic/single cell and biofilms. The most effective derivatives were tested on preformed S. aureus biofilms and against Gram-negative bacteria Acinetobacter baumannii and Pseudomonas aeruginosa, using fingolimod as the reference compound. Seven derivatives were more effective against S. aureus, while five other derivatives showed improved activity against P. aeruginosa and/or A. baumannii, with no apparent change in cytotoxicity on human cells. The most interesting derivatives, compounds 43 and 55, displayed a broader spectrum of antibacterial activity, possibly exerted by the change of the para-hydrocarbon chain to a meta position for 43 and by an additional hydroxyl group for 55.

Repurposing the Sphingosine-1-Phosphate Receptor Modulator Etrasimod as an Antibacterial Agent Against Gram-Positive Bacteria

“…Inhibiting QS is an interesting alternative approach to reduce the drug use in infections involving biofilms, as preventing biofilm formation maintains bacteria in a more susceptible planktonic state. The QS inhibitory activity of fingolimod and its derivatives has been previously demonstrated by our group ( Gilbert-Girard et al, 2020b ; Zore et al, 2021 ). To investigate whether etrasimod could also act as quorum sensing inhibitor (QSI), we tested it using a previously described C. violaceum platform ( Skogman et al, 2016 ).…”

“…In a previous study, we found that fingolimod, an FDA-approved drug for the treatment of relapsing-remitting multiple sclerosis, has antibacterial and anti-biofilm activity against Staphylococcus aureus ( Gilbert-Girard et al, 2020b ). Medicinal chemistry efforts by our group provided further insights on structure-activity relationships and yielded several fingolimod derivatives with more potent antibacterial activity ( Zore et al, 2021 ). Fingolimod is a structural analogue of sphingosine, a sphingoid base naturally found in mammalian cells, which has a well reported antimicrobial activity.…”

Fingolimod synergizes and reverses K. pneumoniae resistance to colistin

“…Consequently, there is a burgeoning interest in identifying synergistic adjuvants for colistin to solve the problem of MDR bacteria ( Kim and Eom, 2021 ). Although FLD exhibits potent antibacterial activity on Gram-positive bacteria, its bactericidal activity on Gram-negative bacteria was not strong ( Zore et al, 2021 ). FLD as an antibiotic adjuvant was rarely studied to enhance the efficacy of antibiotics.…”

Tetrandrine Derivatives as Promising Antibacterial Agents

“…For this reason, new strategies are necessary both for the management of antibiotics and for the development of new antibacterial agents with fewer side effects . Among the natural sources, animal and vegetal extracts, metabolites of microbial origin, e.g., defense enzymes, and organic acids, and secondary metabolites from plants, such as phytoalexins, saponins, terpenoids, phenolics, alkaloids, etc., have been successfully tested as potential antibacterial agents. − In this regard, alkaloids are a group of promising antibacterial agents, as they can be recovered from many sources and have a broad antibacterial spectrum with good activity against common clinical strains, including multidrug-resistant bacteria. Within this group, the isoquinoline alkaloids, those with an isoquinoline skeleton, have been very attractive to the scientific community and have therefore been extensively studied .…”