Chemical and Biological Engineering, University of Colorado Boulder, Boulder, CO 80303, USA.
Renewable and Sustainable Energy Institute, University of Colorado Boulder, Boulder, CO 80303, USA.
Sci Adv. 2017 Oct 4;3(10):e1701776. doi: 10.1126/sciadv.1701776. eCollection 2017 Oct.
The rise of multidrug-resistant (MDR) bacteria is a growing concern to global health and is exacerbated by the lack of new antibiotics. To treat already pervasive MDR infections, new classes of antibiotics or antibiotic adjuvants are needed. Reactive oxygen species (ROS) have been shown to play a role during antibacterial action; however, it is not yet understood whether ROS contribute directly to or are an outcome of bacterial lethality caused by antibiotics. We show that a light-activated nanoparticle, designed to produce tunable flux of specific ROS, superoxide, potentiates the activity of antibiotics in clinical MDR isolates of , , and . Despite the high degree of antibiotic resistance in these isolates, we observed a synergistic interaction between both bactericidal and bacteriostatic antibiotics with varied mechanisms of action and our superoxide-producing nanoparticles in more than 75% of combinations. As a result of this potentiation, the effective antibiotic concentration of the clinical isolates was reduced up to 1000-fold below their respective sensitive/resistant breakpoint. Further, superoxide-generating nanoparticles in combination with ciprofloxacin reduced bacterial load in epithelial cells infected with serovar Typhimurium and increased survival upon infection with serovar Enteriditis, compared to antibiotic alone. This demonstration highlights the ability to engineer superoxide generation to potentiate antibiotic activity and combat highly drug-resistant bacterial pathogens.
多药耐药（MDR）细菌的出现对全球健康构成了越来越大的威胁，而新抗生素的缺乏则加剧了这一问题。为了治疗已经普遍存在的 MDR 感染，需要新型抗生素或抗生素佐剂。已证明活性氧（ROS）在抗菌作用中起作用；然而，目前尚不清楚 ROS 是否直接有助于或是否是抗生素引起的细菌致死的结果。我们表明，一种光激活的纳米颗粒，旨在产生可调通量的特定 ROS，超氧阴离子，增强了临床 MDR 分离株中的抗生素的活性，包括 、 和 。尽管这些分离株具有高度的抗生素耐药性，但我们观察到杀菌和抑菌抗生素之间存在协同相互作用，这些抗生素具有不同的作用机制，我们的超氧阴离子产生纳米颗粒在超过 75%的组合中存在协同相互作用。由于这种增效作用，临床分离株的有效抗生素浓度降低了 1000 倍以下，低于各自的敏感/耐药临界点。此外，与单独使用抗生素相比，超氧化物产生的纳米颗粒与环丙沙星联合使用可减少上皮细胞感染 血清型 Typhimurium 后的细菌负荷，并增加感染 血清型 Enteriditis 后的 存活率。这一发现强调了工程超氧化物产生以增强抗生素活性并对抗高度耐药的细菌病原体的能力。
