Armengol E, Domenech O, Fusté E, Pérez-Guillén I, Borrell J H, Sierra J M, Vinas M
Laboratory of Molecular Microbiology and Antimicrobials, Department of Pathology and Experimental Therapeutics, School of Medicine, University of Barcelona, Barcelona, Spain.
Department of Pharmacy, Pharmaceutical Technology and Physical-Chemistry, University of Barcelona, Barcelona, Spain.
Infect Drug Resist. 2019 Jul 11;12:2031-2038. doi: 10.2147/IDR.S207844. eCollection 2019.
Despite its use was abandoned several decades ago, the polycationic peptide colistin has become the last hope to treat severe infections caused by multidrug-resistant Gram-negative bacteria. Thus, the development of colistin resistance may seriously compromise the efficacy of treatment. Moreover, colistin has high toxicity being dose dependent. A potentially effective strategy to avoid resistance may be to combine colistin with other antimicrobials. This may help in the rescue of old antimicrobials and in reducing toxic undesired effects.
Antimicrobial susceptibility determination, efflux machinery function measurements in different conditions and measurement of inhibition of the extrusion by colistin were performed. Moreover, modifications of anisotropy of the membranes by using fluorescent dyes was accomplished.
Sub-inhibitory concentrations of colistin have a synergistic effect with several antimicrobials that act intracellularly (targeting protein synthesis and DNA replication). This effect was demonstrated through the uptake increases of acridine orange. in and but also in an intrinsically colistin-resistant species as . Measurements of the anisotropy of bacterial membranes, as a measure of membrane fluidity, showed significant changes indicative of colistin activity.
The alterations in the cellular efflux machinery that resulted in higher intracellular concentrations of acridine orange, and likely of other antimicrobials combined with data of membrane fluidity and measured synergism in vitro allow us to envisage the use of these combinations to fight infections caused by multidrug-resistant bacteria.
尽管多阳离子肽黏菌素在几十年前就已被弃用，但它已成为治疗多重耐药革兰氏阴性菌引起的严重感染的最后希望。因此，黏菌素耐药性的产生可能会严重影响治疗效果。此外，黏菌素具有剂量依赖性的高毒性。避免耐药性的一种潜在有效策略可能是将黏菌素与其他抗菌药物联合使用。这可能有助于挽救旧的抗菌药物并减少不良毒性作用。
进行了抗菌药敏测定、在不同条件下测量外排机制功能以及测量黏菌素对药物外排的抑制作用。此外，还通过使用荧光染料实现了对膜各向异性的修饰。
黏菌素的亚抑制浓度与几种作用于细胞内的抗菌药物（靶向蛋白质合成和DNA复制）具有协同作用。通过吖啶橙摄取量的增加证明了这种作用，在[具体菌种1]和[具体菌种2]中如此，在一种固有黏菌素耐药的菌种[具体菌种3]中也是如此。作为膜流动性指标的细菌膜各向异性测量显示出表明黏菌素活性的显著变化。
细胞外排机制的改变导致吖啶橙以及可能其他抗菌药物的细胞内浓度升高，再结合膜流动性数据和体外测量的协同作用，使我们能够设想使用这些联合用药来对抗多重耐药细菌引起的感染。
