Design, synthesis and biological properties of amphiphilic aminoglycosides
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Date
2019
Authors
Yang, Xuan
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Abstract
Antibiotic resistance is a serious threat to human health, as we are facing the emergence of pathogens resistant to all available antibiotics. Amphiphilic aminoglycosides (AAGs) are an emerging source of antibacterials to combat infections caused by antibiotic-resistant bacteria; however, we found that they can also play a role as antibiotic adjuvants in combination therapies. In this study, a new series of amphiphilic aminoglycoside-based (AG-based) adjuvants, tobramycin-based efflux pump inhibitor conjugates, tobramycin-based lysine peptoid conjugates, and nebramine-based conjugates, have been successfully developed. In vitro combination studies indicate the ability of these AG-based conjugates to potentiate multiple classes of legacy antibiotics particularly to tetracyclines, fluoroquinolones, and rifampicin against multidrug-resistant (MDR) Gram-negative bacilli. We also demonstrated in vivo that combinations of selected AG-based conjugates and certain legacy antibiotics (minocycline or rifampicin) protect Galleria mellonella larvae from the lethal effects of MDR Pseudomonas aeruginosa. Mode of action studies indicate that these AG-based conjugates appear to possess intrinsic physicochemical properties that induce multimodal effects including permeabilization of the bacterial outer membrane, depolarization of the inner membrane, and dissipation of the proton motive force (PMF), which energizes efflux pumps. In addition, we discovered AAGs can also boost the innate immune response that may be exploited therapeutically. The amphiphilic tobramycins are capable of inducing the production of the chemokine IL-8, which plays a critical role in 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. Thus, AAGs represent a promising avenue for the development of multifunctional molecules or antibiotic adjuvants for the prevention or treatment of bacterial infections.
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Keywords
Amphiphilic aminoglycoside, Gram-negative bacteria, Antibiotic, Combination study, Immunomodulatory properties