LEGO-Lipophosphonoxins: A Novel Approach in Designing Membrane Targeting Antimicrobials

The alarming rise of bacterial antibiotic resistance
requires the
development of new compounds. Such compounds, lipophosphonoxins (LPPOs),
were previously reported to be active against numerous bacterial species,
but serum albumins abolished their activity. Here we describe the
synthesis and evaluation of novel antibacterial compounds termed LEGO-LPPOs,
loosely based on LPPOs, consisting of a central linker module with
two attached connector modules on either side. The connector modules
are then decorated with polar and hydrophobic modules. We performed
an extensive structure–activity relationship study by varying
the length of the linker and hydrophobic modules. The best compounds
were active against both Gram-negative and Gram-positive species including
multiresistant strains and persisters. LEGO-LPPOs act by first depleting
the membrane potential and then creating pores in the cytoplasmic
membrane. Importantly, their efficacy is not affected by the presence
of serum albumins. Low cytotoxicity and low propensity for resistance
development demonstrate their potential for therapeutic use.