PDF(Pubmed)
Abstract：
The inappropriate and inconsistent use of antibiotics in combating multidrug-resistant bacteria exacerbates their drug resistance through a few distinct pathways. Firstly, these bacteria can accumulate multiple genes, each conferring resistance to a specific drug, within a single cell. This accumulation usually takes place on resistance plasmids (R). Secondly, multidrug resistance can arise from the heightened expression of genes encoding multidrug efflux pumps, which expel a broad spectrum of drugs from the bacterial cells. Additionally, bacteria can also eliminate or destroy antibiotic molecules by modifying enzymes or cell walls and removing porins. A significant limitation of traditional multidrug therapy lies in its inability to guarantee the simultaneous delivery of various drug molecules to a specific bacterial cell, thereby fostering incremental drug resistance in either of these paths. Consequently, this approach prolongs the treatment duration. Rather than using a biologically unimportant coformer in forming cocrystals, another drug molecule can be selected either for protecting another drug molecule or, can be selected for its complementary activities to kill a bacteria cell synergistically. The development of a multidrug cocrystal not only improves tabletability and plasticity but also enables the simultaneous delivery of multiple drugs to a specific bacterial cell, philosophically perfecting multidrug therapy. By adhering to the fundamental tenets of multidrug therapy, the synergistic effects of these drug molecules can effectively eradicate bacteria, even before they have the chance to develop resistance. This approach has the potential to shorten treatment periods, reduce costs, and mitigate drug resistance. Herein, four hypotheses are presented to create complementary drug cocrystals capable of simultaneously reaching bacterial cells, effectively destroying them before multidrug resistance can develop. The ongoing surge in the development of novel drugs provides another opportunity in the fight against bacteria that are constantly gaining resistance to existing treatments. This endeavour holds the potential to combat a wide array of multidrug-resistant bacteria.
摘要：
抗生素在对抗多重耐药细菌中的不适当和不一致的使用通过一些不同的途径加剧了它们的耐药性。首先,这些细菌可以积累多个基因，每个都赋予对特定药物的抗性，在一个细胞内。这种积累通常发生在抗性质粒(R)上。其次,多药耐药性可由编码多药外排泵的基因表达升高引起，从细菌细胞中排出广谱的药物。此外,细菌还可以通过修饰酶或细胞壁和去除孔来消除或破坏抗生素分子。传统多药疗法的一个显著局限性在于它不能保证各种药物分子同时递送到特定的细菌细胞,从而在这两种途径中都促进了耐药性的增加。因此,这种方法延长了治疗时间。而不是使用生物学上不重要的共形成物来形成共晶，可以选择另一种药物分子来保护另一种药物分子，或者，可以选择其互补活性以协同杀死细菌细胞。多药共晶体的开发不仅提高了成片性和可塑性，而且能够将多种药物同时递送到特定的细菌细胞，在哲学上完善多种药物治疗。通过坚持多种药物治疗的基本原则，这些药物分子的协同作用可以有效根除细菌，甚至在他们有机会产生抵抗力之前。这种方法有可能缩短治疗期，降低成本,减轻耐药性。在这里，提出了四个假设来创建能够同时到达细菌细胞的补充药物共晶，在多药耐药性发展之前有效地摧毁它们。新药开发的持续激增为对抗不断对现有治疗产生抗药性的细菌提供了另一个机会。这项努力具有对抗多种耐多药细菌的潜力。
