A new family of small molecules targets anionic phospholipid found in bacterial membrane
Antibiotic resistance is one of the most serious threats to human health according to the World Health Organization (WHO). Antibacterial resistance has been around since the development of antibiotics, it is a part of bacterial evolution. The rapid increase in drug-resistant infections is evidence that antibiotics are becoming less effective to kill 'Superbugs'. To overcome the problems from Superbugs, we endeavor to develop more potent and new class of small molecules called LIPTINS. Bacterial plasma membranes are rich in anionic Phosphatidylglycerol (PG), however it is not widely found in eukaryotes. Thus, PG is a potential target for selective antibacterial therapeutics. We have prepared a family of target-based designed multifunctional Liptins that bind to the PG head group. The binding pocket of Liptin was complementary for the lipid head group and interacts with both the phosphate anion portion and neutral glycerol portion of the PG lipid head group. Following the synthesis and purification, the Liptins were subjected to binding studies with tetrabutylammonium phosphatidylglycerol anions (TBAPG) monitored with both proton NMR spectroscopy and isothermal titration calorimetry (ITC) to reveal the binding stoichiometry and binding thermodynamics between each Liptin and the TBAPG in solution. Efflux experiments with liposomes containing 20% PG / 80% PE lipids demonstrate the fluorescence dye leakage when liptin binds to PG an increase in the membrane permeability. The antibacterial activity of Liptin was identified by in-vitro experiments MIC, MBC, membrane depolarization, Live/Dead with Gram-positive and Gram-negative organisms. Upon binding to PG within the bacterial plasma membrane, the Liptin-PG complex alters the lipid head group size and charge, disrupting physicochemical properties of the bacterial plasma membrane. This leads to lowered bacterial cell viability and cell growth.
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