Patel Neha, Swavey Shawn, Robinson Jayne
Department of Biology, University of Dayton, Dayton, OH 45469, USA.
Department of Chemistry, University of Dayton, Dayton, OH 45469, USA.
Antibiotics (Basel). 2020 Dec 6;9(12):875. doi: 10.3390/antibiotics9120875.
One of the greatest threats to human health is the rise in antibiotic-resistant bacterial infections. (PsA) is an "opportunistic" pathogen known to cause life-threatening infections in immunocompromised individuals and is the most common pathogen in adults with cystic fibrosis (CF). We report here a cationic zinc (II) porphyrin, ZnPor, that effectively kills planktonic and biofilm-associated cells of PsA. In standard tests against 16-18 h-old biofilms, concentrations as low as 16 µg/mL resulted in the extensive disruption and detachment of the matrix. The pre-treatment of biofilms for 30 min with ZnPor at minimum inhibitory concentration (MIC) levels (4 µg/mL) substantially enhanced the ability of tobramycin (Tobra) to kill biofilm-associated cells. We demonstrate the rapid uptake and accumulation of ZnPor in planktonic cells even in dedicated heme-uptake system mutants (ΔPhu, ΔHas, and the double mutant). Furthermore, uptake was unaffected by the ionophore carbonyl cyanide m-chlorophenyl hydrazine (CCCP). Cells pre-exposed to ZnPor took up the cell-impermeant dye SYTOX Green in a concentration-dependent manner. The accumulation of ZnPor did not result in cell lysis, nor did the cells develop resistance. Taken together, these properties make ZnPor a promising candidate for treating multi-drug-resistant infections, including persistent, antibiotic-resistant biofilms.
对人类健康最大的威胁之一是抗生素耐药性细菌感染的增加。洋葱伯克霍尔德菌（PsA）是一种“机会性”病原体，已知会在免疫功能低下的个体中引起危及生命的感染，并且是患有囊性纤维化（CF）的成年人中最常见的病原体。我们在此报告一种阳离子锌（II）卟啉ZnPor，它能有效杀死PsA的浮游细胞和生物膜相关细胞。在针对16 - 18小时龄生物膜的标准测试中，低至16μg/mL的浓度会导致基质广泛破坏和脱落。用最低抑菌浓度（MIC）水平（4μg/mL）的ZnPor对生物膜进行30分钟预处理，可显著增强妥布霉素（Tobra）杀死生物膜相关细胞的能力。我们证明即使在专门的血红素摄取系统突变体（ΔPhu、ΔHas和双突变体）中，ZnPor在浮游细胞中也能快速摄取和积累。此外，摄取不受离子载体羰基氰化物间氯苯腙（CCCP）的影响。预先暴露于ZnPor的细胞以浓度依赖的方式摄取细胞不透性染料SYTOX Green。ZnPor的积累不会导致细胞裂解，细胞也不会产生耐药性。综上所述，这些特性使ZnPor成为治疗包括持续性、抗生素耐药性生物膜在内的多重耐药感染的有希望的候选药物。
