The University of Queenslandgrid.1003.2, School of Chemistry and Molecular Biosciences, Australian Infectious Diseases Research Centre, Brisbane, QLD, Australia.
The University of Queenslandgrid.1003.2, UQ Centre for Clinical Research, Australian Infectious Diseases Research Centre, Brisbane, QLD, Australia.
mBio. 2022 Feb 22;13(1):e0351721. doi: 10.1128/mbio.03517-21. Epub 2022 Jan 11.
Acinetobacter baumannii causes high mortality in ventilator-associated pneumonia patients, and antibiotic treatment is compromised by multidrug-resistant strains resistant to β-lactams, carbapenems, cephalosporins, polymyxins, and tetracyclines. Among COVID-19 patients receiving ventilator support, a multidrug-resistant A. baumannii secondary infection is associated with a 2-fold increase in mortality. Here, we investigated the use of the 8-hydroxyquinoline ionophore PBT2 to break the resistance of A. baumannii to tetracycline class antibiotics. , the combination of PBT2 and zinc with either tetracycline, doxycycline, or tigecycline was shown to be bactericidal against multidrug-resistant A. baumannii, and any resistance that did arise imposed a fitness cost. PBT2 and zinc disrupted metal ion homeostasis in A. baumannii, increasing cellular zinc and copper while decreasing magnesium accumulation. Using a murine model of pulmonary infection, treatment with PBT2 in combination with tetracycline or tigecycline proved efficacious against multidrug-resistant A. baumannii. These findings suggest that PBT2 may find utility as a resistance breaker to rescue the efficacy of tetracycline-class antibiotics commonly employed to treat multidrug-resistant A. baumannii infections. Within intensive care unit settings, multidrug-resistant (MDR) Acinetobacter baumannii is a major cause of ventilator-associated pneumonia, and hospital-associated outbreaks are becoming increasingly widespread. Antibiotic treatment of A. baumannii infection is often compromised by MDR strains resistant to last-resort β-lactam (e.g., carbapenems), polymyxin, and tetracycline class antibiotics. During the on-going COVID-19 pandemic, secondary bacterial infection by A. baumannii has been associated with a 2-fold increase in COVID-19-related mortality. With a rise in antibiotic resistance and a reduction in new antibiotic discovery, it is imperative to investigate alternative therapeutic regimens that complement the use of current antibiotic treatment strategies. Rescuing the efficacy of existing therapies for the treatment of MDR A. baumannii infection represents a financially viable pathway, reducing time, cost, and risk associated with drug innovation.
鲍曼不动杆菌导致呼吸机相关性肺炎患者死亡率高，而对β-内酰胺类、碳青霉烯类、头孢菌素类、多黏菌素和四环素类抗生素耐药的多药耐药菌株会影响抗生素治疗效果。在接受呼吸机支持的 COVID-19 患者中，继发于多重耐药鲍曼不动杆菌的感染与死亡率增加 2 倍相关。在这里，我们研究了 8-羟基喹啉离子载体 PBT2 用于打破鲍曼不动杆菌对四环素类抗生素耐药性的作用。结果表明，PBT2 与锌联合使用，与四环素、多西环素或替加环素联合使用，对多药耐药鲍曼不动杆菌具有杀菌作用，任何产生的耐药性都会带来适应性成本。PBT2 和锌破坏了鲍曼不动杆菌的金属离子内稳态，增加了细胞内锌和铜的含量，同时减少了镁的积累。在肺部感染的小鼠模型中，PBT2 与四环素或替加环素联合治疗对多药耐药鲍曼不动杆菌有效。这些发现表明，PBT2 可能具有作为耐药逆转剂的潜力，以恢复四环素类抗生素治疗多药耐药鲍曼不动杆菌感染的疗效。在重症监护病房环境中，多药耐药（MDR）鲍曼不动杆菌是呼吸机相关性肺炎的主要原因，医院相关的暴发越来越普遍。鲍曼不动杆菌感染的抗生素治疗常常受到对最后一线β-内酰胺（如碳青霉烯类）、多黏菌素和四环素类抗生素耐药的 MDR 菌株的影响。在正在进行的 COVID-19 大流行期间，继发于鲍曼不动杆菌的细菌感染与 COVID-19 相关死亡率增加 2 倍相关。随着抗生素耐药性的增加和新抗生素发现的减少，有必要研究替代治疗方案，以补充当前抗生素治疗策略的使用。恢复现有疗法治疗 MDR 鲍曼不动杆菌感染的疗效具有经济可行性，可减少与药物创新相关的时间、成本和风险。
