Minocycline and Silver Dual-Loaded Polyphosphoester-Based Nanoparticles for Treatment of Resistant Pseudomonas aeruginosa
Minocycline and Silver Dual-Loaded Polyphosphoester-Based Nanoparticles for Treatment of Resistant Pseudomonas aeruginosa
复制标题
DOI：
10.1021/acs.molpharmaceut.8b01288
复制
发表时间：
2019-04-01
影响因子：
4.9
通讯作者：
Cannon, Carolyn L.
中科院分区：
文献类型：
--
作者：
Chen, Qingquan;Shah, Kush N.;Cannon, Carolyn L.
大约 50% 的囊性纤维化 (CF) 患者（包括 20% 的成人 CF 患者）肺部检测到铜绿假单胞菌。这些成年患者中的大多数都携带多重耐药（MDR）菌株，限制了可用的治疗选择。银长期以来被用作广谱抗菌剂，耐药发生率低。尽管毒性低，但银阳离子的可用性较差，需要高剂量才能有效根除感染。为了解决银的这一缺点，纳米颗粒已被用作传输装置来改善治疗效果。此外，研究表明，仔细的剂量校准和高效的递送系统的协同组合可产生优异的抗菌活性，同时避免两种疗法的潜在副作用。在此，通过高通量筛选，4-表米诺环素（米诺环素的一种代谢物）被鉴定为针对铜绿假单胞菌的活性抗菌剂。体外评估了 4-表米诺环素、米诺环素和醋酸银对从 CF 患者获得的铜绿假单胞菌临床分离株的抗菌活性。接下来，使用棋盘测定法研究银/米诺环素组合针对铜绿假单胞菌分离株的协同活性，并通过终点菌落形成单位测定测定法进行鉴定。最后，在体外评估了共负载米诺环素和银的纳米颗粒的抗菌活性。结果表明，银和米诺环素单独使用时都是有效的抗菌剂，并且组合可以减少两种治疗剂的剂量以达到相同的抗菌效果。此外，所提出的协同银/米诺环素组合可以作为下一代抗生素共同装载到纳米颗粒中，以对抗 MDR 病原体带来的威胁。
Pseudomonas aeruginosa has been detected in the lungs of similar to 50% of patients with cystic fibrosis (CF), including 20% of adult CF patients. The majority of these adult patients harbor multi-drug resistant (MDR) strains, limiting the available treatment options. Silver has long been used as a broad-spectrum antimicrobial agent with a low incidence of resistance. Despite low toxicity, poor availability of silver cations mandates a high dosage to effectively eradicate infections. To address this shortcoming of silver, nanoparticles have been used as delivery devices to improve treatment outcomes. Furthermore, studies have demonstrated that synergistic combinations with careful dose calibrations and efficient delivery systems result in superior antimicrobial activity while avoiding potential side effects of both therapeutics. Here 4-epi-minocycline, a metabolite of minocycline, was identified as an active antimicrobial against P. aeruginosa using a high-throughput screen. The antimicrobial activities of 4-epiminocycline, minocycline, and silver acetate against clinical isolates of P. aeruginosa obtained from CF patients were evaluated in vitro. Next, the synergistic activity of the silver/minocycline combination against P. aeruginosa isolates was investigated using checkerboard assays and identified with end-point colony forming unit determination assays. Finally, nanoparticles coloaded with minocycline and silver were evaluated in vitro for antimicrobial activity. The results demonstrated that both silver and minocycline are potent antimicrobials alone and that the combination allows a reduced dosage of both therapeutics to achieve the same antimicrobial effect. Furthermore, the proposed synergistic silver/minocycline combination can be coloaded into nanoparticles as a next-generation antibiotic to combat the threats presented by MDR pathogens.