NSRRC Activity Report 2022

038 NSRRC ACTIVITY REPORT 2022 This report features the work of Ho-Hsiu Chou and his co-workers published in Chem. Eng. J. 438 , 135592 (2022). TPS 44A Quick-scanning X-ray Absorption Spectroscopy TLS 23A1 Small/Wide Angle X-ray Scattering • SAXS, XANES/EXAFS • Soft Matter, Materials Science, Chemistry Reference 1. T.-Y. Han, C.-H. Lin, Y.-S. Lin, C.-M. Yeh, Y.-A. Chen, H.-Y. Li, Y.-T. Xiao, J.-W. Chang, A.-C. Su, U.-S. Jeng, H.-H. Chou, Chem. Eng. J. 438 , 135592 (2022). Polytherapy to Combat Antimicrobial-Resistant Bacteria Polytherapy of antibiotic and lipid nanoparticles could be an alternative to fight against superbugs. G ram-negative bacteria have caused significant diseases and have increasingly become one of the leading causes of high morbidity and mortality globally, which has led to the extensive development of antibiotics that are effectively against such bacteria. However, bacteria evolve new features and develop antibiotic resistance faster than the development of new antibiotics. Fortunately, nanosized particles can lower the treatment dose while maintaining high antimicrobial activities. This raises the hope that nanoparticles could reduce the probability of promoting resistant bacteria compared with conventional antibiotics. Accordingly, lipid nanoparticles, due to their high biocompatibility and ability to solubilize hydrophobic and hydrophilic molecules, have received considerable attention in the field of biological applications as drug carriers. These particles without exception simply function as nano vehicles that deliver the loaded cargo to the bacteria. Comparative studies have evidenced the superiority of polytherapy regimens of polymyxins with various drugs approved by the U.S. Food and Drug Administration over their corresponding monotherapies, either by producing an improved combination effect or, conversely, by achieving the same killing effect using lower doses of medicines, while diminishing or delaying the development of resistance. Therefore, superbugs can be effectively combatted via the polytherapy of antibiotics with lipid nanoparticles. Hsin-Hui Shen’s group (Monash University, Australia) recently conducted a study to investigate why the polytherapy of polymyxin B (PMB) with cubosomes exhibited better antibacterial activity than the traditional PMB-loaded cubosomes ( Fig. 1 ). 1 Neutron reflectometry (NR) data was measured by the PLATYPUS time-of-flight neutron reflectometer at Australia’s Nuclear Science and Technology Organisation (ANSTO). NR was used to investigate the interaction between the components of the polytherapy treatment and a model outer membrane (OM) of gram-negative bacteria ( Figs. 2(a) and 2(b) ). Shen’s team found that the PMB-loaded cubosomes could simply attach to the bilayer surface without further penetrating ( Figs. 2(c) and 2(d) ), most likely due to the diffused cubosome layer preventing the released PMB from binding to the membrane. Therefore, the bacterial membrane remained relatively intact. Additionally, two distinct modes of action were found for the antibacterial activity of the polytherapy ( Figs. 2(e) and 2(f) ). Firstly, the interaction between the positively charged PMB and negatively charged phosphate groups on lipid A was driven by electrostatic force, which led to membrane stability. Secondly, the partially permeabilized membrane facilitated the entry of the cubosomes into the bilayer, which were Fig. 1 : Schematic diagram of polymyxin B-loaded cubosomes and interaction of the polytherapy treatment with the gram- negative bacterial outer membrane. [Reproduced from Ref. 1]