title: Designing Simple Lipidated Lysines: Bifurcation Imparts Selective Antibacterial Activity.
abstract: In the global effort to thwart antimicrobial resistance, lipopeptides are an important class of antimicrobial agents, especially against Gram-negative infections. In an attempt to circumvent their synthetic complexities, we designed simple membrane-active agents involving only one amino acid and two lipid tails. Herein we show that the use of two short lipid tails instead of a single long one significantly increases selective antibacterial activity. This study yielded several selective antibacterial compounds, and investigations into the properties of this compound class were conducted with the most active compound. Fluorescence spectroscopic studies revealed the capacity of the representative compound to cause depolarization and permeabilization of bacterial cell membranes. This membrane-active nature of the compound imparts superior activity against persister cells, biofilms, and planktonic cells. Topical application of the compound decreased bacterial burden in mice inflicted with burn-infections caused by Acinetobacter baumannii. We anticipate that the design principles described herein will direct the development of several antimicrobial agents of clinical importance.
authors.affiliation: Chemical Biology and Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Jakkur, Bengaluru, 560064, Karnataka, India.
authors.forename: Chandradhish
authors.initials: C
authors.lastname: Ghosh
authors.affiliation: Chemical Biology and Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Jakkur, Bengaluru, 560064, Karnataka, India.
authors.forename: Mohini Mohan
authors.initials: MM
authors.lastname: Konai
authors.affiliation: Chemical Biology and Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Jakkur, Bengaluru, 560064, Karnataka, India.
authors.forename: Paramita
authors.initials: P
authors.lastname: Sarkar
authors.affiliation: Chemical Biology and Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Jakkur, Bengaluru, 560064, Karnataka, India.
authors.forename: Sandip
authors.initials: S
authors.lastname: Samaddar
authors.affiliation: Chemical Biology and Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Jakkur, Bengaluru, 560064, Karnataka, India.
authors.forename: Jayanta
authors.initials: J
authors.lastname: Haldar
keywords: antibiotics; antimicrobial resistance; biofilms; drug design; peptidomimetics