De Oliveira David M P, Keller Bernhard, Hayes Andrew J, Ong Cheryl-Lynn Y, Harbison-Price Nichaela, El-Deeb Ibrahim M, Li Gen, Keller Nadia, Bohlmann Lisa, Brouwer Stephan, Turner Andrew G, Cork Amanda J, Jones Thomas R, Paterson David L, McEwan Alastair G, Davies Mark R, McDevitt Christopher A, Itzstein Mark von, Walker Mark J
Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia.
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia.
Antibiotics (Basel). 2022 Mar 25;11(4):449. doi: 10.3390/antibiotics11040449.
Gram-positive bacteria do not produce lipopolysaccharide as a cell wall component. As such, the polymyxin class of antibiotics, which exert bactericidal activity against Gram-negative pathogens, are ineffective against Gram-positive bacteria. The safe-for-human-use hydroxyquinoline analog ionophore PBT2 has been previously shown to break polymyxin resistance in Gram-negative bacteria, independent of the lipopolysaccharide modification pathways that confer polymyxin resistance. Here, in combination with zinc, PBT2 was shown to break intrinsic polymyxin resistance in (Group A ; GAS), (including methicillin-resistant ), and vancomycin-resistant . Using the globally disseminated M1T1 GAS strain 5448 as a proof of principle model, colistin in the presence of PBT2 + zinc was shown to be bactericidal in activity. Any resistance that did arise imposed a substantial fitness cost. PBT2 + zinc dysregulated GAS metal ion homeostasis, notably decreasing the cellular manganese content. Using a murine model of wound infection, PBT2 in combination with zinc and colistin proved an efficacious treatment against streptococcal skin infection. These findings provide a foundation from which to investigate the utility of PBT2 and next-generation polymyxin antibiotics for the treatment of Gram-positive bacterial infections.
革兰氏阳性菌不会产生脂多糖作为细胞壁成分。因此，对革兰氏阴性病原体具有杀菌活性的多粘菌素类抗生素对革兰氏阳性菌无效。先前已表明，对人类安全使用的羟基喹啉类似物离子载体PBT2可打破革兰氏阴性菌的多粘菌素耐药性，这与赋予多粘菌素耐药性的脂多糖修饰途径无关。在此，与锌联合使用时，PBT2被证明可打破A组链球菌（GAS）、金黄色葡萄球菌（包括耐甲氧西林金黄色葡萄球菌）和耐万古霉素肠球菌的固有多粘菌素耐药性。使用全球传播的M1T1 GAS菌株5448作为原理验证模型，结果表明在PBT2 + 锌存在的情况下，黏菌素具有杀菌活性。任何产生的耐药性都会带来巨大的适应性代价。PBT2 + 锌使GAS金属离子稳态失调，显著降低细胞内锰含量。使用伤口感染小鼠模型，PBT2与锌和黏菌素联合使用被证明是治疗链球菌皮肤感染的有效方法。这些发现为研究PBT2和下一代多粘菌素抗生素在治疗革兰氏阳性菌感染方面的效用奠定了基础。
