Small-Molecular Adjuvants with Weak Membrane Perturbation Potentiate Antibiotics against Gram-Negative Superbugs
Small-Molecular Adjuvants with Weak Membrane Perturbation Potentiate Antibiotics against Gram-Negative Superbugs
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DOI：
10.1021/acsinfecdis.2c00092
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发表时间：
2022-05-13
影响因子：
5.3
通讯作者：
Haldar, Jayanta
中科院分区：
文献类型：
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作者：
Dhanda, Geetika;Mukherjee, Riya;Haldar, Jayanta
与膜靶向化合物的联合治疗是最前沿的，因为考虑到细菌膜在各种多药耐药元件中的作用，细菌膜是一个有吸引力的靶标。然而，这种策略被与这些药剂相关的毒性所削弱。对于膜靶向抗生素增效剂或佐剂，尚未探索最佳膜扰动和最小毒性的结构要求。在这里，我们报告了不同的化学基团对膜扰动，活性，毒性和增强能力的去甲亚精胺衍生物的结构影响。在这份报告中已经表明，弱膜扰动，实现了环状疏水部分的掺入，是一种有效的策略来设计抗生素佐剂，可以忽略不计的体外毒性和活性，但良好的增效能力。发现芳基或金刚烷官能化衍生物是与无环类似物相反的更好的手段，表现出多个类别的抗生素对关键革兰氏阴性超级细菌的高达4096倍的增强。增强的机制是非特异性的，包括弱外膜透化，膜去极化，和外排抑制。这种通过在具有游离胺基的化学设计中并入环状疏水部分而“弱扰动膜”的独特概念作为无毒膜扰动佐剂的突破，并且具有恢复废弃抗生素治疗复杂的革兰氏阴性细菌感染的效果的潜力。
Combination therapy with membrane-targeting compounds is at the forefront because the bacterial membrane is an attractive target considering its role in various multidrug-resistant elements. However, this strategy is crippled by the toxicity associated with these agents. The structural requirements for optimum membrane perturbation and minimum toxicity have not been explored for membrane-targeting antibiotic potentiators or adjuvants. Here, we report the structural influence of different chemical moieties on membrane perturbation, activity, toxicity, and potentiating ability in norspermidine derivatives. It has been shown in this report that weak membrane perturbation, achieved by the incorporation of cyclic hydrophobic moieties, is an effective strategy to design antibiotic adjuvants with negligible in vitro toxicity and activity but good potentiating ability. Aryl or adamantane functionalized derivatives were found to be better resorts as opposed to the acyclic analogues, exhibiting as high as 4096-fold potentiation of multiple classes of antibiotics toward critical Gram-negative superbugs. The mechanism of potentiation was nonspecific, consisting of weak outer-membrane permeabilization, membrane depolarization, and efflux inhibition. This unique concept of "weakly perturbing the membrane" by incorporating cyclic hydrophobic moieties in a chemical design with free amine groups serves as a breakthrough for nontoxic membrane-perturbing adjuvants and has the potential to revitalize the effect of obsolete antibiotics to treat complicated Gram negative bacterial infections.