Escobedo Humberto D, Zawadzki Nicholas, Till James K A, Vazquez-Torres Andres, Wang Guankui, Simberg Dmitri, Orlicky David J, Johnson Joshua, Guess Marsha K, Nair Devatha P, Schurr Michael J
Department of Pharmaceutical Science, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Department of Obstetrics and Gynecology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Nanomedicine. 2025 Apr;65:102812. doi: 10.1016/j.nano.2025.102812. Epub 2025 Feb 28.
Among hospital-acquired infections, Pseudomonas aeruginosa-associated urinary tract infections (UTIs) are mainly caused by indwelling urethral catheters (catheter-associated UTIs or CAUTIs) and are difficult to treat, resulting in high rates of morbidity among hospitalized patients. While antibiotics can successfully treat bacteria in the bladder lumen, they are inefficient at crossing stratified urothelium plasma membranes to kill persistent intracellular bacterial communities (IBCs). Herein, we introduce an approach to target UTI IBCs by locally delivering the antibiotic gentamicin via polymeric nanogels conjugated with a cell-penetrating peptide Cys-Gly-Lys-Arg-Lys. This novel approach delivered ~36 % more intracellular gentamicin compared to drug delivered in solution in vitro. In an acute UTI murine model, the nanogel cell-penetrating peptide drug delivery system facilitated the transport of gentamicin into the urothelium and resulted in >90 % clearance of a uropathogenic P. aeruginosa clinical strain in vivo.
在医院获得性感染中，铜绿假单胞菌相关的尿路感染（UTIs）主要由留置导尿管引起（导管相关尿路感染或CAUTIs），且难以治疗，导致住院患者发病率很高。虽然抗生素可以成功治疗膀胱腔内的细菌，但它们在穿过分层的尿路上皮细胞膜以杀死持续存在的细胞内细菌群落（IBCs）方面效率低下。在此，我们介绍一种通过与细胞穿透肽Cys-Gly-Lys-Arg-Lys偶联的聚合物纳米凝胶局部递送抗生素庆大霉素来靶向UTI IBCs的方法。与体外溶液给药相比，这种新方法使细胞内庆大霉素递送量增加了约36%。在急性UTI小鼠模型中，纳米凝胶细胞穿透肽药物递送系统促进了庆大霉素向尿路上皮的转运，并在体内使致病性铜绿假单胞菌临床菌株的清除率超过90%。
