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.

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.Toassess whether AAGs also induce host-directed immunomodulatory responses,w ed etermined 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.M oreover,A AGsc an selectively control inflammatory responses induced in the presence of endotoxins to prevent septic shock.Inconclusion, 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.The world is facing an enormous threat from the emergence and dissemination of bacteria that are resistant to almost all currently available antibiotics. [1,2] Twos trategies,m ultiplecomponent antibiotic adjuvants [3] and single-componentbased antibacterial polypharmacology [4] are currently under investigation to combat bacterial resistance.B oth strategies seek to exploit multiple modes of action. Recently,a mphiphilic aminoglycosides (AAGs) have emerged as as ource of antibacterial agents to combat bacterial resistance. [5][6][7][8][9][10][11][12][13][14] Modeof-action studies have shown that AAGs can show different modes of action [9,[11][12][13] to AGs, which bind to the 30S ribosomal subunit, thereby leading to the disruption of protein synthesis. [15] Fori nstance,i tw as shown that the antibacterial effect of an eamine-based AAGa gainst P. aeruginosa was caused by changes in membrane depolarization and permeability and not by inhibition of protein synthesis. [9,11] Strong evidence for membrane-targeting inter-actions of AAGs were also reported for amphiphilic neomycin and tobramycin analogues. [12,13] Encouraged by the multimodal activity of cationic amphiphilic host-defense peptides (HDPs) in the host-directed clearance of an infection, [16][17][18] we developed an interest in exploring whether AAGs can show HDP-like properties. AAGs that combine direct antibacterial effects with the induction of immunomodulatory responses in host immune cells may display superior efficacy against multiple-drugresistant (MDR) bacteria. It is noteworthy that for cationic amphiphilic HDPs like LL-37, the direct antibacterial activity is antagonized by physiological concentrations of divalent cations and polyanions,and other host factors. [16,17] However, HDP-mediated protection has been observed in several in vivo infection models,t hus suggesting that the broad range of immunomodulatory activities exhibited by these peptides is the predominant function of HDPs for the resolution of microbial infections. [17,[19][20][21] With this in ...