S-thanatin functionalized liposome potentially targeting on Klebsiella pneumoniae and its application in sepsis mouse model

Abstract

S-thanatin (Ts) was a short antimicrobial peptide with selective antibacterial activity. In this study, we aimed to design a drug carrier with specific bacterial targeting potential. The positively charged Ts was modified onto the liposome surface by linking Ts to the constituent lipids via a PEG linker. The benefits of this design were evaluated by preparing a series of liposomes and comparing their biological effects in vitro and in vivo. The particle size and Zeta potential of the constructed liposomes were measured with a Zetasizer Nano ZS system and a confocal laser scanning microscope. The in vitro drug delivery potential was evaluated by measuring the cellular uptake of encapsulated levofloxacin using HPLC. Ts-linked liposome or its conjugates with quantum dots favored bacterial cells, and increased the bacterial uptake of levofloxacin. In antimicrobial assays, the Ts and levofloxacin combination showed a synergistic effect, and Ts-LPs-LEV exhibited excellent activity against the quality control stain Klebsiella pneumoniae ATCC 700603 and restored the susceptibility of multidrug-resistant K. pneumoniae clinical isolates to levofloxacin in vitro. Furthermore, Ts-LPs-LEV markedly reduced the lethality rate of the septic shock and resulted in rapid bacterial clearance in mouse models receiving clinical multidrug resistant (MDR) isolates. These results suggest that the Ts-functionalized liposome may be a promising antibiotic delivery system for clinical infectious disorders caused by MDR bacteria, in particular the sepsis related diseases.

Nanotools for Sepsis Diagnosis and Treatment

“…In another study, Fan et al designed S-thanatin (Ts)functionalized levofloxacin (LEV)-encapsulated liposomes (LPs) to target and eliminate clinical MDR isolates of K. pneumoniae in vitro and in vivo ( Figure 8A). [94] Ts is a novel antimicrobial peptide that exhibits selective antimicrobial activity independent of current drug resistance and has a binding affinity to LPS. [95,96] LPs are known to serve as carriers for antibiotics in order to improve pharmacokinetics.…”

“…Simultaneously, Ts enhanced targeting capacity and perturbed the lipid membrane bilayers of bacteria, which consequently catalyzed membrane permeability of LPs-LEV and strong antibacterial activity. In a septic shock mouse model, Ts incorporation resulted in superior bacterial clearance in blood to free LEV and LPs-LEV and in increased survival rate with 93.3% of treated animals surviving at 72 h. [94] Yunus Basha et al conjugated cyclodextrin-complexed rifampicin and LEV to curdlan-based NPs to accomplish elimination of Mycobacterium smegmatis macrophages (MACs). [100] Curdlan is a linear glucan, known for its immunomodulatory and antimicrobial properties and it is recognized by dectin-1 receptor expression in MACs.…”

Advancements on the molecular design of nanoantibiotics: current level of development and future challenges

“…33 A liposomal complex containing the phospholipid cardiolipin co-entrapped with levofloxacin was formulated by Gaidukevich et al to suppress the growth of Mycobacterium tuberculosis and reduce the minimum inhibitory concentration of cardiolipin (33.5 μM) and levofloxacin up to 2 μg ml −1 . 34 Antimicrobial activities of herbal extracts with lysozyme were evaluated against two Gram-positive (B. subtilis and M. luteus) and two Gram-negative (E. coli and S. marcescens) bacteria by Matouskova et al 35 The integration of selective antimicrobial peptides such as S-thanatin onto liposomes with encapsulated levofloxacin via a lipid PEG linker was recently reported by Fan et al 36 ( Fig. 3B).…”

Arrranjos supramoleculares de lípide catiônico, antibióticos e polímeros: preparação, caracterização e atividade contra bactérias multirresistentes e micobactérias de crescimento rápido

“…A combinação, em um mesmo arranjo, de compostos que agem em diferentes alvos na célula microbiana é uma maneira interessante de criar um "coquetel" (Fan et al, 2015). Foi proposto o seguinte mecanismo de ação para estes lipossomos de levofloxacino e S-tanatina: os lipossomos interagem com os compostos negativamente carregados da superfície celular bacteriana (como lipopolissacarídeos), então eles fundem-se com a membrana externa da bactéria,…”

“…interferindo com a integridade da membrana, permitindo maior entrada de levofloxacino na célula e ainda dificultando a ação de bombas de efluxo (Furneri et al, 2000;Fan et al, 2015). Outro composto utilizado na combinação com antimicrobianos para o preparo de arranjos contra micro-organismos multirresistentes é a piperina (Khameneh et al, 2015).…”