Center for Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, 9401 Jeronimo Road, Irvine, CA 92618-1908, United States.
Curr Top Med Chem. 2018;18(22):1926-1936. doi: 10.2174/1568026619666181129141524.
The menace of multi-drug resistance by bacterial pathogens that are responsible for infectious diseases in humans and animals cannot be over-emphasized. Many bacteria develop resistance to antibiotics by one or more combination of resistance mechanisms namely, efflux pump activation thereby reducing bacteria intracellular antibiotic concentration, synthesizing a protein that protects target site causing poor antibiotic affinity to the binding site, or mutations in DNA and topoisomerase gene coding that alters residues in the binding sites. The ability to use a combination of these resistance mechanisms among others creates a phenomenon known as antimicrobial drug resistance. The development of a new class of antibiotics to address bacterial resistance will require many resources, such as time-consuming effort and high cost associated with commercial risk. Hence, the researchers have adopted a strategic approach to enhance the antibacterial efficacy of existing antibiotics by conjugation or combination of existing antibiotics. A number of peptides have become known as antibacterial, cell-penetrating, or membrane-active agents. Antibiotics-Peptide Conjugates (APCs) are a combination of known antibiotics with a peptide connected through a linker. The rationale is to produce an alternative multifunctional antimicrobial compound that will elicit synergistic antibacterial activities while reducing known shortcomings of antibiotics or peptides, such as cellular penetration, serum instability, cytotoxicity, hemolysis, and instability in high salt conditions. In this review, we overview APCs which are used, as a strategy to combat the menace of multi-drug resistance of bacterial pathogens. Furthermore, we explain the focus area of adopted APC strategies and physicochemical properties data that show how they can be used to improve antibacterial efficacy.
细菌病原体对抗生素的多重耐药性威胁，不能被过分强调。许多细菌通过一种或多种耐药机制对抗生素产生耐药性，例如激活外排泵，从而降低细菌内的抗生素浓度，合成一种保护靶位的蛋白质，导致抗生素与结合位点的亲和力降低，或改变 DNA 和拓扑异构酶基因编码的突变，从而改变结合位点的残基。这些耐药机制的组合能力创造了一种被称为抗菌药物耐药性的现象。开发一类新的抗生素来解决细菌耐药性问题，需要投入许多资源，例如与商业风险相关的耗时费力和高成本。因此，研究人员采取了一种战略方法，通过共轭或组合现有的抗生素来提高现有抗生素的抗菌效果。许多肽已被称为抗菌、细胞穿透或膜活性剂。抗生素-肽缀合物 (APC) 是通过连接子连接的已知抗生素与肽的组合。其基本原理是产生一种替代的多功能抗菌化合物，既能产生协同抗菌活性，又能降低抗生素或肽的已知缺点，如细胞穿透性、血清不稳定性、细胞毒性、溶血和高盐条件下的不稳定性。在这篇综述中，我们概述了 APC 作为对抗细菌病原体多药耐药性威胁的一种策略。此外，我们还解释了采用 APC 策略的重点领域和物理化学性质数据，展示了它们如何用于提高抗菌效果。
