Lysine-Based Small Molecules That Disrupt Biofilms and Kill both Actively Growing Planktonic and Nondividing Stationary Phase Bacteria

Abstract

The emergence of bacterial resistance is a major threat to global health. Alongside this issue, formation of bacterial biofilms is another cause of concern because most antibiotics are ineffective against these recalcitrant microbial communities. Ideal future antibacterial therapeutics should possess both antibacterial and anti-biofilm activities. In this study we engineered lysine-based small molecules, which showed not only commendable broad-spectrum antibacterial activity but also potent biofilm-disrupting properties. Synthesis of these lipophilic lysine-norspermidine conjugates was achieved in three simple reaction steps, and the resultant molecules displayed potent antibacterial activity against various Gram-positive (Staphylococcus aureus, Enterococcus faecium) and Gram-negative bacteria (Escherichia coli) including drug-resistant superbugs MRSA (methicillin-resistant S. aureus), VRE (vancomycin-resistant E. faecium), and β-lactam-resistant Klebsiella pneumoniae. An optimized compound in the series showed activity against planktonic bacteria in the concentration range of 3-10 μg/mL, and bactericidal activity against stationary phase S. aureus was observed within an hour. The compound also displayed about 120-fold selectivity toward both classes of bacteria (S. aureus and E. coli) over human erythrocytes. This rapidly bactericidal compound primarily acts on bacteria by causing significant membrane depolarization and K(+) leakage. Most importantly, the compound disrupted preformed biofilms of S. aureus and did not trigger bacterial resistance. Therefore, this class of compounds has high potential to be developed as future antibacterial drugs for treating infections caused by planktonic bacteria as well as bacterial biofilms.

Threats to adhesive/dentin interfacial integrity and next generation bio‐enabled multifunctional adhesives

“…) . Lysine has been widely used in biomaterials and studies have revealed its antibacterial properties and biofilm‐disrupting activity . When incorporated in the adhesive formulation, this essential amino acid could buffer the interfacial micro‐environment without leaching amine‐containing cytotoxic species.…”

Modulating pH through lysine integrated dental adhesives

“…Its lipophilic derivatives, lysine-based small molecules, showed commendable broad-spectrum antibacterial activity and biofilm-disrupting activity [21]. A recent study also showed that the residue of lysine may have antibacterial properties [22].…”

Design and Solution‐Phase Synthesis of Membrane‐Targeting Lipopeptides with Selective Antibacterial Activity

“…Almost no treatment regimens exist to treat infections caused by multidrug-resistant strainso ft hese deadly pathogens. [22][23][24][25][26][27][28][29][30] Event houghm any of these synthetic lipopeptidesw ere potent against bacteria, a big caveat was their unimpressives electivity towards bacteria over mammalian cells. Therefore, to tackle these drug-resistant bacteria, there is ac riticaln eed for new classes of broad-spectrum antibacterial agentsw ith new mechanism of action.…”

“…[32] Furthermore, such issuesa st oxicitya nd stabilityl imit their broadscale usages in clinic.T oa ddress the above-mentioned limitations,t he scientific community responded with diverse classes of synthetic mimics of lipopeptides. [22][23][24][25][26][27][28][29][30] Event houghm any of these synthetic lipopeptidesw ere potent against bacteria, a big caveat was their unimpressives electivity towards bacteria over mammalian cells. Quite notably,t he preparationo fm ost of the existing lipopeptidesr equires olid-phase synthesis, which left considerable space for the development of new class of lipopeptidesw ith simpler synthetic designs and more selectivea ntibacteriala ctivity.…”