Precision Dosing of Antibiotics and Potentiators by Hypoxia-Responsive Nanoparticles for Overcoming Antibiotic Resistance in Gram-Negative Bacteria

Abstract

The stalling development of antibiotics, especially against intrinsically resistant Gram-negative pathogens associated with outer membranes, leads to an emerging antibiotic crisis across the globe. To breathe life into existing drugs, we herein report a hypoxia-responsive nanoparticle (NP) that encapsulates a hydrophobic antibiotic, rifampicin, and a cationic potentiator, polysulfonium. The simultaneous release of antibiotics and potentiators can be promoted and inhibited in response to the severity of bacterial-induced hypoxia, leading to antimicrobial dosing in a precision manner. Under the synergism of polysulfoniums with membrane-disruption capability, the NPs can intensively decrease the antibiotic dose by up to 66−95% in eliminating planktonic Gram-negative P. aeruginosa bacteria and achieve an 8-log reduction of bacteria in mature biofilms at rifampicin MIC. The NP formulation demonstrates that precision dosing of antibiotics and potentiators regulated by hypoxia provides a promising strategy to maximize efficacy and minimize toxicity in treating Gram-negative bacterial infection.

A universal strategy to enhance photothermal conversion efficiency by regulating the molecular aggregation states for safe photothermal therapy of bacterial infections

“…[1][2][3] While the advent of antibiotics marked a significant turning point, the misuse of these drugs has led to the rapid development of drug resistance among bacteria. [4][5][6][7] As a result, there is an urgent need for the development of antibiotic-independent treatments for bacterial infections. [8][9][10][11] In view of the non-invasive attribute, high selectivity, deep tissue penetration, less drug resistance, and broad-spectrum antibacterial properties, near-infrared (NIR)-based photothermal therapy (PTT) has emerged as a pivotal approach for effectively combating drug-resistant bacterial infections.…”