Quaternization of fluoroquinolones – novel permanently ionized antibacterials active against biofilms

Increasing antimicrobial resistance poses a critical problem to public health. Many strategies are engaged to combat this problem; one of them is the synthesis of hybrid drugs consisting of diverse bioactive parts merged into one molecule [1]. The risk that bacteria will mutate and evolve defense mechanisms is lower since the various pharmacophoric parts act against different molecular targets.

We developed a new class of fluoroquinolone-quaternary ammonium conjugates to obtain inhibitors of bacterial topoisomerases with membrane destabilization activity [2]. Docking studies revealed that compounds can interact with topoisomerases in the fluoroquinolone-binding mode. Hybrids were screened against Gram-positive and negative bacteria, including pathogens from the ESKAPE group and antibiotic-resistant strains, in planktonic and biofilm forms. The most effective were moderately lipophilic (CHI 10-20) cyclopropyl-substituted molecules [3]. Moreover, novel compounds exhibit negligible cytotoxicity.

The Project was financed by the Polish National Agency for Academic Exchange as a part of the Bekker Scholarship Programme.

[1] Fedorowicz, J.; Sączewski, J. Modifications of quinolones and fluoroquinolones: hybrid compounds and dual-action molecules. Monatsh Chem 2018, 149,1199–1245. https://doi.org/10.1007/s00706-018-2215-x

[2] Fedorowicz, J.; Sączewski, J.; Konopacka, A.; Waleron, K.; Lejnowski, D.; Ciura, K.; Tomašič, T.; Skok, Ž.; Savijoki, K.; Morawska, M.; Gilbert-Girard, S.; Fallarero, A. Synthesis and biological evaluation of hybrid quinolone-based quaternary ammonium antibacterial agents, Eur. J. Med. Chem. 2019, 179, 576-590, https://doi.org/10.1016/j.ejmech.2019.06.071

[3] Ciura, K.; Fedorowicz, J.; Kapica, H.; Adamkowska, A.; Sawicki, W.; Sączewski, J. Affinity of Fluoroquinolone–Safirinium Dye Hybrids to Phospholipids Estimated by IAM-HPLC. Processes 2020, 8, 1148. https://doi.org/10.3390/pr8091148