Amphiphilic Tobramycins with Immunomodulatory Properties

Abstract

Amphiphilic aminoglycosides (AAGs) are an emerging source of antibacterials to combat infections caused by antibiotic-resistant bacteria. Mode-of-action studies indicate that AAGs predominately target bacterial membranes, thereby leading to depolarization and increased permeability. To assess whether AAGs also induce host-directed immunomodulatory responses, we determined the AAG-dependent induction of cytokines in macrophages in the absence or presence of lipopolysaccharide (LPS). Our results show for the first time that AAGs can boost the innate immune response, specifically the recruitment of immune cells such as neutrophils required for the resolution of infections. Moreover, AAGs can selectively control inflammatory responses induced in the presence of endotoxins to prevent septic shock. In conclusion, our study demonstrates that AAGs possess multifunctional properties that combine direct antibacterial activity with host-directed clearance effects reminiscent of those of host-defense peptides.

Cationic Amphiphiles Induce Macromolecule Denaturation and Organelle Decomposition in Pathogenic Yeast

“…Membranes are essential for the viability of all cells and therefore are attractive targets for the development of antibiotics,a lthough very few antimicrobial agents that act by disrupting the microbial cell membrane are in clinical use. [1,2] One of the obstacles to rational design of membrane disrupting agents is the lack of detailed understanding of their mode of action. Unlike many known antimicrobial drugs that act by binding primarily to awell-defined domain in aprotein target, cell disrupting agents can potentially act on numerous sites on the surface and in the cytosol of the microbial cell.…”

Guiding Drugs to Target‐Harboring Organelles: Stretching Drug‐Delivery to a Higher Level of Resolution

“…[24] Cationic antimicrobial peptides (CAPs) are produced by numerous organisms to combat microbial infections.C APs self-assemble and form pores in the microbesp lasma membrane leading to membrane permeabilization and cell death. [32][33][34][35][36][37][38] Thed esign of these antimicrobial agents is based on the attachment of membrane-anchoring hydrophobic residues to an aminoglycoside scaffold that is positively charged under physiological conditions.Antibiotics from the aminoglycoside class perturb the fidelity of bacterial translation by binding to the decoding A-site region of the bacterial ribosome;h owever, their target site is shifted from the ribosome to the plasma membrane through conjugation to one or more hydrophobic residues. [31] Thec hemical composition principles learned from the study of CAPs have been used to design several types of synthetic membrane-disrupting agents.I nr ecent years,s everal research groups have been engaged in the development of membrane-disrupting cationic amphiphiles derived from aminoglycosides.…”

Amphiphilic lysine conjugated to tobramycin synergizes legacy antibiotics against wild‐type and multidrug‐resistant Pseudomonas aeruginosa

“…Similarly, amphiphilic aminoglycosides are known to disrupt bacterial membranes . Moreover, we recently reported that some amphiphilic aminoglycosides may possess beneficial immunomodulatory properties . In preliminary work, we recently demonstrated that amphiphilic lysines conjugated to tobramycin strongly synergized minocycline and rifampicin against antibiotic‐resistant P. aeruginosa .…”