Polymyxin B‐Polysaccharide Polyion Nanocomplex with Improved Biocompatibility and Unaffected Antibacterial Activity for Acute Lung Infection Management

Abstract

The decade‐old antibiotic, polymyxin B (PMB), is regarded as the last line defense against gram‐negative “superbug.” However, the serious nephrotoxicity and neurotoxicity strongly obstruct further application of this highly effective antibiotic. Herein, a charge switchable polyion nanocomplex exhibiting pH‐sensitive property is proposed to deliver PMB which is expected to improve the biosafety of PMB on the premise of retaining excellent antibacterial activity. The polyion nanocomplex is prepared through electrostatic interaction of positively charged PMB and negatively charged 2,3‐dimethyl maleic anhydride (DA) grafted chitoligosaccharide (CS). The negative charge of CS‐DA will convert to positive due to the hydrolysis of amide bonds in acidic infectious environment, leading to the disassembly of CS‐DA/PMB nanocomplex and release of PMB. CS‐DA/PMB nanocomplex does not show significant toxicity to mammalian cells while retaining excellent bactericidal capability equivalent to free PMB. The nephrotoxicity and neurotoxicity of CS‐DA/PMB dramatically decrease compared to free PMB. Moreover, CS‐DA/PMB nanocomplex exhibits superior bactericidal activity against Pseudomonas aeruginosa in an acute lung infection mouse model. The pH‐sensitive polyion nanocomplexes may provide a new way to reduce the side effects of highly toxic antibiotics without reducing their intrinsic antibacterial activity, which is the key factor to achieve extensive in vivo clinical applications.

Aggregation‐Induced Emission‐Based Platforms for the Treatment of Bacteria, Fungi, and Viruses

“…Besides above discussed charge‐induced bactericidal behavior, bacteria are also sensitive to many other bactericidal agents, including ROS and antibiotics. [ 128–131 ] Sasmal et al. fabricated a special iridium (Ir)‐based AIEgen which could produce ROS for bacterial elimination.…”

Application of Polymeric Nanocarriers for Enhancing the Bioavailability of Antibiotics at the Target Site and Overcoming Antimicrobial Resistance

“…Unfortunately, the high nephrotoxicity and neurotoxicity occurring during systemic polymyxin therapy strongly limited its clinical applications. To address this issue, Chai et al reported a charge switchable polyion nanocomplex with a pH-sensitive property to improve polymyxin's biosafety while retaining its excellent antibacterial activity (Figure 4A) [48]. The nanocomplex was prepared through electrostatic interaction of positively charged polymyxin B and negatively charged 2,3-dimethyl maleic anhydride-grafted chitoligosaccharide.…”

“…The NPs were prepared through electrostatic interaction of positively charged PMB and negatively charged 2,3-dimethyl maleic anhydride (DA)-grafted chitoligosaccharide (CS). (2) Schematics of in vivo drug safety, different from free PMB and CS-DA/PMB, and the mechanism of antibacterial activity of CS-DA/PMB (reprinted with permission from[48], copyright 2020 John Wiley and Sons). (B) The self-assembly structure and mode of action of acidic pH-sensitive micelles in delivering antibacterials in cariogenic dental biofilms (adapted with permission from(19), copyright 2015 ACS).…”

Visualizing the Potential Impairment of Polymyxin B to Central Nervous System Through MR Susceptibility-Weighted Imaging

“…The ability of PMB to modify or disrupt lipid membranes may help explain the toxic vulnerability of high-fat neurons ( Chai et al, 2020 ; Fu et al, 2020 ). Its neurotoxicity is thought to be caused by the direct interaction of PMB with neurons, and the interaction of PMB with neurons causes dose-dependent neurotoxicity.…”