Efflux pump system-mediated bacterial multidrug resistance is one of the main causes of antibiotic failure. Therefore, it is necessary to develop a novel nanocarrier that could effectively inhibit drug-resistant bacteria by increasing the intake and retention time of antibiotics. Herein, we constructed a pH-responsive nanocarrier (MSN@FA@CaP@FA) with double folic acid (FA) and calcium phosphate (CaP) covered on the surface of mesoporous silica (MSN) by electrostatic attraction and biomineralization, respectively. Afterward, loading the nanocomposites with ampicillin (Amp) effectively increased the uptake and reduced the efflux effect in Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) by the specific targeting of FA. Moreover, Amp-MSN@FA@CaP@FA could specifically transport Amp to the bacterial infection site. Similarly, antibacterial experiments revealed that the Amp-MSN@FA@CaP@FA could significantly enhance the activity of Amp for inhibiting drug-resistant bacteria, without producing drug resistance. Additionally, the Amp-MSN@FA@CaP@FA could reduce the content of protein and inhibit the protein activity in drug-resistant bacteria, so that it destroyed the bacterial membrane and led to the bacteria death. In vivo antibacterial experiments showed that the Amp-MSN@FA@CaP@FA could effectively reduce the mortality of drug-resistant E. coli infection and promote wound healing of drug-resistant S. aureus infection. In summary, Amp-MSN@FA@CaP@FA has a potential for application in sustained-release nanostructures and to inhibit drug-resistant bacteria.

中文翻译：

---

装有Amp的具有pH响应能力的叶酸修饰的介孔二氧化硅纳米颗粒，可通过克服外排泵系统来增强抗耐药细菌的功效†

外排泵系统介导的细菌多药耐药性是抗生素失效的主要原因之一。因此，有必要开发一种新型的纳米载体，其可以通过增加抗生素的摄取和保留时间来有效抑制耐药菌。在此，我们构建了一种pH响应纳米载体（MSN @ FA @ CaP @ FA），其双叶酸（FA）和磷酸钙（CaP）通过静电吸引和生物矿化作用分别覆盖在中孔二氧化硅（MSN）的表面上。之后，用氨苄西林（Amp）负载纳米复合材料可有效增加大肠杆菌（E. coli）和金黄色葡萄球菌（S. aureus）的吸收并降低其外排作用。），以FA的特定定位为准。此外，Amp-MSN @ FA @ CaP @ FA可以将Amp专门运送到细菌感染部位。同样，抗菌实验表明，Amp-MSN @ FA @ CaP @ FA可以显着增强Amp抑制耐药菌的活性，而不会产生耐药性。另外，Amp-MSN @ FA @ CaP @ FA可以减少耐药细菌中的蛋白质含量并抑制其蛋白质活性，从而破坏细菌膜并导致细菌死亡。体内抗菌实验表明，Amp-MSN @ FA @ CaP @ FA可以有效降低耐药性大肠杆菌感染的死亡率，促进耐药性金黄色葡萄球菌的伤口愈合。感染。总之，Amp-MSN @ FA @ CaP @ FA具有在缓释纳米结构中应用和抑制耐药菌的潜力。