Impact of Intrinsic Resistance Mechanisms on Potency of QPX7728, a New Ultrabroad-Spectrum Beta-Lactamase Inhibitor of Serine and Metallo-Beta-Lactamases in Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii
Impact of Intrinsic Resistance Mechanisms on Potency of QPX7728, a New Ultrabroad-Spectrum Beta-Lactamase Inhibitor of Serine and Metallo-Beta-Lactamases in Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii
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DOI：
10.1128/aac.00552-20
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发表时间：
2020-06-01
影响因子：
4.9
通讯作者：
Dudley, Michael N.
中科院分区：
文献类型：
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作者：
Lomovskaya, Olga;Nelson, Kirk;Dudley, Michael N.
QPX7728是一种超广谱的硼酸β-内酰胺酶抑制剂，在使用纯化的酶进行生化分析时，它在纳摩尔浓度范围内对关键的丝氨酸和金属β-内酰胺酶具有抑制作用。在生化实验中观察到的QPX7728的广谱抑制活性转化为许多β-内酰胺类药物对产生β-内酰胺酶的目标病原菌的效力增强。利用产KPC-3的肺炎克雷伯菌、铜绿假单胞菌和产OXA-23的鲍曼不动杆菌的不同外排和孔蛋白突变组合的等基因板，确定细菌外排和通透性对抑菌效力的影响。无论是肠杆菌科细菌还是非发酵菌，如铜绿假单胞菌或鲍曼不动杆菌，QPX7728几乎不受多重耐药外排泵的影响。外膜被通透后，QPX7728对铜绿假单胞菌的抑制作用进一步增强。QPX7728对铜绿假单胞菌的杀灭作用不受碳青霉烯菌孔蛋白OprD灭活的影响。虽然OmpK36(但不是OmpK35)的变化降低了QPX7728的效力(8-16倍)，但QPX7728(4微克/毫升)仍然完全逆转了孔蛋白突变菌株中KPC介导的美罗培南耐药性，这与这些突变对QPX7728效力的影响比其他药物小的情况是一致的。超广谱β-内酰胺酶抑制谱结合多种对外排和通透性内在耐药机制敏感的β-内酰胺类抗生素的活性增强，表明QPX7728是一种有用的与多种β-内酰胺类抗生素联合使用的抑制剂。
QPX7728 is an ultrabroad-spectrum boronic acid beta-lactamase inhibitor that demonstrates inhibition of key serine and metallo-beta-lactamases at a nanomolar concentration range in biochemical assays with purified enzymes. The broad-spectrum inhibitory activity of QPX7728 observed in biochemical experiments translates into enhancement of the potency of many beta-lactams against strains of target pathogens producing beta-lactamases. The impacts of bacterial efflux and permeability on inhibitory potency were determined using isogenic panels of KPC-3-producing isogenic strains of Klebsiella pneumoniae and Pseudomonas aeruginosa and OXA-23-producing strains of Acinetobacter baumannii with various combinations of efflux and porin mutations. QPX7728 was minimally affected by multidrug resistance efflux pumps either in Enterobacteriaceae or in nonfermenters, such as P. aeruginosa or A. baumannii. Against P. aeruginosa, the potency of QPX7728 was further enhanced when the outer membrane was permeabilized. The potency of QPX7728 against P. aeruginosa was not affected by inactivation of the carbapenem porin OprD. While changes in OmpK36 (but not OmpK35) reduced the potency of QPX7728 (8- to 16-fold), QPX7728 (4 mu g/ml) nevertheless completely reversed the KPC-mediated meropenem resistance in strains with porin mutations, consistent with the lesser effect of these mutations on the potency of QPX7728 compared to that of other agents. The ultrabroad-spectrum beta-lactamase inhibition profile, combined with enhancement of the activity of multiple beta-lactam antibiotics with various sensitivities to the intrinsic resistance mechanisms of efflux and permeability, indicates that QPX7728 is a useful inhibitor for use with multiple beta-lactam antibiotics.