A novel approach to designing antimicrobial compounds
The alarming rise of bacterial antibiotic resistance requires the development of new compounds. Such compounds, lipophosphonoxins (LPPOs) from Dominik Rejman Group at IOCB Prague, were previously reported to be active against numerous bacterial species, but serum albumins abolished their activity.
Researchers led by Dominik Rejman and Libor Krásný from the Institute of Microbiology in collaboration with colleagues from Charles University and Palacký University Olomouc have now designed, synthesized, and characterized a novel type of these antibacterial compounds termed linker-evolved-group-optimized-LPPOs (LEGO-LPPOs).
LEGO-LPPOs are active against both Gram-positive and -negative bacteria, in addition to multi-drug resistant strains and persisters. Importantly, serum albumins are not affecting LEGO-LPPOs activity. The molecules act by depleting the membrane potential followed by cytoplasmic membrane pores creation.
In vitro and in vivo skin and eye irritability tests with selected LEGO-LPPOs proved their safety for potential topical applications. Furthermore, oral, and subcutaneous administration of the most promising member of the series demonstrated its potential for systemic use.
Original article: Duy Dinh Do Pham et al. LEGO-Lipophosphonoxins: A Novel Approach in Designing Membrane Targeting Antimicrobials. J. Med. Chem. 2022, 65, 14, 10045–10075. https://doi.org/10.1021/acs.jmedchem.2c00684