School of Chemistry and Molecular Biosciences and Australian Infectious Diseases Research Centre, The University of Queensland, Queensland 4072, Australia.
Institute for Glycomics, Griffith University, Queensland 4222, Australia.
Sci Transl Med. 2020 Nov 18;12(570). doi: 10.1126/scitranslmed.abb3791.
The emergence of polymyxin resistance in carbapenem-resistant and extended-spectrum β-lactamase (ESBL)-producing bacteria is a critical threat to human health, and alternative treatment strategies are urgently required. We investigated the ability of the hydroxyquinoline analog ionophore PBT2 to restore antibiotic sensitivity in polymyxin-resistant, ESBL-producing, carbapenem-resistant Gram-negative human pathogens. PBT2 resensitized , , , and to last-resort polymyxin class antibiotics, including the less toxic next-generation polymyxin derivative FADDI-287, in vitro. We were unable to select for mutants resistant to PBT2 + FADDI-287 in polymyxin-resistant containing a plasmid-borne gene or carrying a chromosomal mutation. Using a highly invasive strain engineered for polymyxin resistance through mutation, we successfully demonstrated the efficacy of PBT2 + polymyxin (colistin or FADDI-287) for the treatment of Gram-negative sepsis in immunocompetent mice. In comparison to polymyxin alone, the combination of PBT2 + polymyxin improved survival and reduced bacterial dissemination to the lungs and spleen of infected mice. These data present a treatment modality to break antibiotic resistance in high-priority polymyxin-resistant Gram-negative pathogens.
多黏菌素耐药性在碳青霉烯类耐药和超广谱β-内酰胺酶（ESBL）产生细菌中的出现对人类健康构成了严重威胁，迫切需要替代治疗策略。我们研究了羟基喹啉类似物离子载体 PBT2 恢复多黏菌素耐药、产 ESBL、碳青霉烯类耐药革兰氏阴性人类病原体抗生素敏感性的能力。PBT2 使 、 、 、 对最后一线多黏菌素类抗生素重新敏感，包括毒性较低的下一代多黏菌素衍生物 FADDI-287，在体外。我们无法在含有质粒携带 blaNDM-1 基因或携带染色体 突变的多黏菌素耐药 中选择对 PBT2 + FADDI-287 耐药的突变体。使用通过 突变工程化的高度侵袭性 菌株来实现多黏菌素耐药性，我们成功地证明了 PBT2 +多黏菌素（黏菌素或 FADDI-287）在免疫功能正常的小鼠革兰氏阴性败血症治疗中的疗效。与单独使用多黏菌素相比，PBT2 +多黏菌素的联合使用提高了生存率，并减少了感染小鼠肺部和脾脏的细菌播散。这些数据提供了一种治疗模式，可以打破高优先级多黏菌素耐药革兰氏阴性病原体的抗生素耐药性。
