Rational Design of Dimeric Lysine N-Alkylamides as Potent and Broad-Spectrum Antibacterial Agents

Abstract

Antibiotic resistance is one of the biggest threats to public health, and new antibacterial agents hence are in an urgent need to combat infectious diseases caused by multidrug-resistant (MDR) pathogens. Utilizing dimerization strategy, we rationally designed and efficiently synthesized a new series of small molecule dimeric lysine alkylamides as mimics of AMPs. Evaluation of these mimics against a panel of Gram-positive and Gram-negative bacteria including MDR strains was performed, and a broad-spectrum and potent compound 3d was identified. This compound displayed high specificity toward bacteria over mammalian cell. Time-kill kinetics and mechanistic studies suggest that compound 3d quickly eliminated bacteria in a bactericidal mode by disrupting bacterial cell membrane. In addition, lead compound 3d could inhibit biofilm formation and did not develop drug resistance in S. aureus and E. coli over 14 passages. These results suggested that dimeric lysine nonylamide has immense potential as a new type of novel small molecular agent to combat antibiotic resistance.

Chemical profiling of alkylamides from the "herbal Botox", Acmella oleracea, cultivated in Mizoram and their pharmacological potentials

“…It is accredited to most of the chemical and medicinal properties of the plant including pungency, tingling or burning sensation when the plant is eaten and Botox-like effects (Barbosa et al, 2016;Silveira et al, 2018). In view of the potentials of alkylamides as a source of novel antibiotics (Niu et al, 2018;Chakthong et al, 2019), this study adds to the compendium as A. oleracea extract was effective against a variety of pathogenic bacteria tested.…”

Dimeric γ-AApeptides With Potent and Selective Antibacterial Activity

“…In the United States, 2 million people get infected by antibiotic-resistant infections every year, which is estimated to cause more than 700,000 deaths (Nimmagadda et al, 2017;Wang et al, 2019). Over the last century Grampositive bacteria, especially the notorious methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus epidermidis (MRSE), and vancomycin-resistant E. faecal (VRE), have spread easily and are now becoming the leading cause of bacterial infections within both health-care and community settings (Lee et al, 2018;Niu et al, 2018).…”

“…(Méndez-Samperio, 2014;Teyssières et al, 2016) Previous reports have shown that HDPs, such as indolicidin (Galdiero et al, 2016) and human defensin 5 (Lei et al, 2018), are potential antibiotics based on their membrane disruption (permeabilization and lysis) ability. Unlike conventional antibiotics targeting some specific intracellular and cell wall targets, the main driving force in the selectivity is the electrostatic interaction between HDPs and bacterial membrane (Su et al, 2017;Niu et al, 2018). It is well known that the membrane of bacteria is negatively charged due to the presence of phosphatidylglycerol (PG), whereas mammalian cell membrane consists of zwitterionic sphingomyelin and phosphatidylcholine (PC).…”

“…It is well known that the membrane of bacteria is negatively charged due to the presence of phosphatidylglycerol (PG), whereas mammalian cell membrane consists of zwitterionic sphingomyelin and phosphatidylcholine (PC). In addition, negatively charged lipopolysaccharides (LPS) and lipoteichoic acids (LTA) on the bacterial membrane further contribute to the selectivity of cationic HDPs for their recognition of bacteria cells (Teng et al, 2016a;Nimmagadda et al, 2017;Su et al, 2017;Niu et al, 2018). After initial selective contact with bacteria, lipophilic side chains of amphipathic HDPs could insert into the lipid bilayer to compromise the membrane stability and integrity through multiple modes, leading to eventual bacterial death (Niu et al, 2018).…”

“…In addition, negatively charged lipopolysaccharides (LPS) and lipoteichoic acids (LTA) on the bacterial membrane further contribute to the selectivity of cationic HDPs for their recognition of bacteria cells (Teng et al, 2016a;Nimmagadda et al, 2017;Su et al, 2017;Niu et al, 2018). After initial selective contact with bacteria, lipophilic side chains of amphipathic HDPs could insert into the lipid bilayer to compromise the membrane stability and integrity through multiple modes, leading to eventual bacterial death (Niu et al, 2018). As the interaction is without the use of a specific protein or DNA targets, this mechanism could explain why HDPs have a low propensity to develop drug resistance, at least partially.…”