QPX7728 is a recently discovered ultra-broad-spectrum beta-lactamase inhibitor (BLI) with potent inhibition of key serine and metallo-beta-lactamases. QPX7728 enhances the potency of many beta-lactams, including carbapenems, in beta-lactamase-producing Gram-negative bacteria, including Acinetobacter spp. The potency of meropenem alone and in combination with QPX7728 (1 to 16 μg/ml) was tested against 275 clinical isolates of Acinetobacter baumannii (carbapenem-resistant A. baumannii [CRAB]) collected worldwide that were highly resistant to carbapenems (MIC₅₀ and MIC₉₀ for meropenem, 64 and >64 μg/ml). Addition of QPX7728 resulted in a marked concentration-dependent increase in meropenem potency, with the MIC₉₀ of meropenem alone decreasing from >64 μg/ml to 8 and 4 μg/ml when tested with fixed concentrations of QPX7728 at 4 and 8 μg/ml, respectively. In order to identify the mechanisms that modulate the meropenem-QPX7728 MIC, the whole-genome sequences were determined for 135 isolates with a wide distribution of meropenem-QPX7728 MICs. This panel of strains included 116 strains producing OXA carbapenemases (71 OXA-23, 16 OXA-72, 16 OXA-24, 9 OXA-58, and 4 OXA-239), 5 strains producing NDM-1, one KPC-producing strain, and 13 strains that did not carry any known carbapenemases but were resistant to meropenem (MIC ≥ 4 μg/ml). Our analysis indicated that mutated PBP3 (with mutations localized in the vicinity of the substrate/inhibitor binding site) is the main factor that contributes to the reduction of meropenem-QPX7728 potency. Still, >90% of isolates that carried PBP3 mutations remained susceptible to ≤8 μg/ml of meropenem when tested with a fixed 4 to 8 μg/ml of QPX7728. In the absence of PBP3 mutations, the MICs of meropenem tested in combination with 4 to 8 μg/ml of QPX7728 did not exceed 8 μg/ml. In the presence of both PBP3 and efflux mutations, 84.6% of isolates were susceptible to ≤8 μg/ml of meropenem with 4 or 8 μg/ml of QPX7728. The combination of QPX7728 with meropenem against CRAB isolates with multiple resistance mechanisms has an attractive microbiological profile.

中文翻译：

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超广谱β-内酰胺酶抑制剂QPX7728与美洛培南合用对耐碳青霉烯鲍曼不动杆菌的临床分离株的体外活性。

QPX7728是最近发现的超广谱β-内酰胺酶抑制剂（BLI），可有效抑制关键丝氨酸和金属β-内酰胺酶。QPX7728增强了许多β-内酰胺（包括碳青霉烯）在产生β-内酰胺酶的革兰氏阴性细菌（包括不动杆菌属）中的效力。美罗培南单独和与QPX7728组合的（1到16微克/毫升）的效价对275个临床分离测试鲍曼不动杆菌（耐碳青霉烯类鲍曼不动杆菌[CRAB]）收集全世界的是具有高度耐碳青霉烯类（MIC ₅₀和美罗培南的MIC ₉₀（64和> 64μg/ ml）。QPX7728的添加导致MIC的美罗培南效能显着浓度依赖性增加₉₀当分别以4和8μg/ ml的固定浓度QPX7728进行测试时，单独的美洛培南的美罗培南的含量从> 64μg/ ml降至8和4μg/ ml。为了鉴定调节美罗培南-QPX7728 MIC的机制，确定了具有广泛分布的美罗培南-QPX7728 MIC的135个分离株的全基因组序列。这组菌株包括116个产生OXA碳青霉烯酶的菌株（71 OXA-23、16 OXA-72、16 OXA-24、9 OXA-58和4 OXA-239），5个产生NDM-1的菌株，一个产生KPC的菌株，以及13株未携带任何已知碳青霉烯酶但对美洛培南具有抗药性（MIC≥4μg/ ml）的菌株。我们的分析表明，突变的PBP3（突变位于底物/抑制剂结合位点附近）是导致美洛培南-QPX7728效力降低的主要因素。不过，> 当使用固定的4至8μg/ ml QPX7728进行测试时，携带PBP3突变的分离株中有90％仍对美罗培南≤8μg/ ml敏感。在不存在PBP3突变的情况下，与4至8μg/ ml QPX7728结合测试的美罗培南的MIC不超过8μg/ ml。在同时存在PBP3和外排突变的情况下，有84.6％的分离株对美罗培南≤8μg/ ml和4或8μg/ ml的QPX7728敏感。QPX7728与美罗培南针对具有多种耐药机制的CRAB分离株的组合具有诱人的微生物特性。在同时存在PBP3和外排突变的情况下，有84.6％的分离株对美罗培南≤8μg/ ml和4或8μg/ ml的QPX7728敏感。QPX7728与美罗培南针对具有多种耐药机制的CRAB分离株的组合具有诱人的微生物特性。在同时存在PBP3和外排突变的情况下，有84.6％的分离株对美罗培南≤8μg/ ml和4或8μg/ ml的QPX7728敏感。QPX7728与美罗培南针对具有多种耐药机制的CRAB分离株的组合具有诱人的微生物特性。