Dual-Mechanism Glycolipidpeptide with High Antimicrobial Activity, Immunomodulatory Activity, and Potential Application for Combined Antibacterial Therapy

Abstract

Bacterial drug resistance is becoming increasingly serious, and it is urgent to develop effective antibacterial drugs. Antimicrobial peptides (AMPs), as potential candidates against bacteria, have a broad prospect for development. Herein, a series of AMPs with biological characteristics (net positive charge, amphiphilicity, and α-helix), an AXA motif recognized by membrane bound serine protease type I signal peptidases (SPase I), an FLPII motif to reduce hemolysis, and a monosaccharide motif to improve the stability and activity were designed and synthesized, and among which, the glycolipidpeptide GLP6 (glycosylated LP6 lipopeptide) had excellent antibacterial and immunomodulatory activity, good stability and biocompatibility, and excellent biofilm eradication and membrane penetrating activity. The positively charged spherical aggregates formed by self-assembly of GLP6 could encapsulate tetracycline (TC) to form GLP6@TC with a sustained-release effect, which could enhance the sensitivity of bacteria to the antibiotic and realize combined sterilization. The results of acute peritonitis and bacterial keratitis showed that GLP6@TC had a good combined antibacterial effect and the ability to inhibit interleukin-2 (IL-2), which could significantly reduce the inflammatory response while treating bacterial infection, and it had great potential for application. The results of computer molecular docking showed the AXA motif could effectively bind to SPase I, which was consistent with the results of biological experiments. In general, the study could provide a perspective for the design of AMPs and combined antibacterial therapy.

Turning cationic antimicrobial peptide KR-12 into self-assembled nanobiotics with potent bacterial killing and LPS neutralizing activities

“…This assessment relies on the hydrolysis of ortho -nitrophenyl-β-galactoside (ONPG) by bacterial β-galactosidase, releasing the chromogenic compound o -nitrophenol (ONP) into the extracellular space when pores form in the inner membrane. 36 In Fig. 3C, the KR-12 group showed ONPG saturation in E. coli after about 30 minutes, similar to the control group.…”

“…Gram-negative bacteria have a robust defense mechanism due to their outer membrane (OM), predominantly composed of lipopolysaccharide (LPS), an amphiphilic macromolecule. 36 LPS creates a barrier against hydrophobic molecules and is associated with drug resistance, adhesion, and bacterial invasiveness. To assess E. coli 's OM permeability, we utilized the hydrophobic fluorescent dye 1- N -phenyl naphthyl amine (NPN), which fluoresces upon entering the hydrophobic environment when the OM is compromised.…”

Polysaccharide-Based Coating with Excellent Antibiofilm and Repeatable Antifouling-Bactericidal Properties for Treating Infected Hernia

“…In recent years, there have been numerous efforts to enhance the antimicrobial properties of medical device surfaces to combat bacterial infections; these include various strategies to control slow release with physical adsorption or loading of drugs, such as antibiotic loading, − the use of antimicrobial peptides, , metal nanoparticles, , photodynamic therapy, − and polycationic antimicrobials. − Among these approaches, quaternary ammonium polymers have demonstrated effective bactericidal activity by disrupting the cell membrane of bacteria. They provide the advantages of simple preparation, absence of drug resistance, and long-lasting antibacterial effects .…”

Near-Infrared-Induced NO-Releasing Photothermal Adhesive Hydrogel with Enhanced Antibacterial Properties

“…3−5 The elevating emergence of bacterial infection not only causes mutagenic bacterial metabolites but also leads to cancer. 6 Various disinfectants, like tetracycline, 7 triclosan, 8 amino-glycosides, 9 polymeric nanoparticles, 10 lipid membranes, 11 and metal nanoparticles, 12 are used to inhibit bacterial infections. However, such treatments are often associated with metalinduced toxicity, drug-resistant microbes, and irritant contact dermatitis.…”

“…However, the extensive use of high doses of antibiotics has escalated the development of bacterial multidrug resistance (MDR) in different bacterial strains. – The elevating emergence of bacterial infection not only causes mutagenic bacterial metabolites but also leads to cancer . Various disinfectants, like tetracycline, triclosan, amino-glycosides, polymeric nanoparticles, lipid membranes, and metal nanoparticles, are used to inhibit bacterial infections. However, such treatments are often associated with metal-induced toxicity, drug-resistant microbes, and irritant contact dermatitis. , Therefore, there is an urgent need to design a safe and effective alternative therapy to eradicate the problems for the security of public health.…”