Qpex Biopharma, Inc., San Diego, California, USA
Qpex Biopharma, Inc., San Diego, California, USA.
Antimicrob Agents Chemother. 2020 May 21;64(6). doi: 10.1128/AAC.00212-20.
QPX7728 is an ultrabroad-spectrum boronic acid beta-lactamase inhibitor, with potent inhibition of key serine and metallo-beta-lactamases being observed in biochemical assays. Microbiological studies using characterized strains were used to provide a comprehensive characterization of the spectrum of beta-lactamase inhibition by QPX7728. The MICs of multiple antibiotics administered intravenously only (ceftazidime, piperacillin, cefepime, ceftolozane, and meropenem) and orally bioavailable antibiotics (ceftibuten, cefpodoxime, tebipenem) alone and in combination with QPX7728 (4 μg/ml), as well as comparator agents, were determined against panels of laboratory strains of and expressing over 55 diverse serine and metallo-beta-lactamases. QPX7728 significantly enhanced the potency of antibiotics against strains expressing class A extended-spectrum beta-lactamases (CTX-M, SHV, TEM, VEB, PER) and carbapenemases (KPC, SME, NMC-A, BKC-1), consistent with the beta-lactamase inhibition demonstrated in biochemical assays. It also inhibited both plasmidic (CMY, FOX, MIR, DHA) and chromosomally encoded (P99, PDC, ADC) class C beta-lactamases and class D enzymes, including carbapenemases, such as OXA-48 from and OXA enzymes from (OXA-23/24/72/58). QPX7728 is also a potent inhibitor of many class B metallo-beta-lactamases (NDM, VIM, CcrA, IMP, and GIM but not SPM or L1). Addition of QPX7728 (4 μg/ml) reduced the MICs for a majority of the strains to the level observed for the control with the vector alone, indicative of complete beta-lactamase inhibition. The ultrabroad-spectrum beta-lactamase inhibition profile makes QPX7728 a viable candidate for further development.
QPX7728 是一种超广谱硼酸β-内酰胺酶抑制剂，在生化测定中观察到对关键丝氨酸和金属β-内酰胺酶有很强的抑制作用。使用经过特征鉴定的菌株进行的微生物学研究用于全面描述 QPX7728 对β-内酰胺酶抑制的广谱性。静脉内给药的多种抗生素（头孢他啶、哌拉西林、头孢吡肟、头孢洛扎烷和美罗培南）和口服生物利用度抗生素（头孢布烯、头孢泊肟、替比培南）单独和联合 QPX7728（4μg/ml）以及对照剂的 MIC 针对表达超过 55 种不同丝氨酸和金属β-内酰胺酶的 和 实验室菌株进行了测定。QPX7728 显著增强了抗生素对表达 A 类扩展谱β-内酰胺酶（CTX-M、SHV、TEM、VEB、PER）和碳青霉烯酶（KPC、SME、NMC-A、BKC-1）的菌株的效力，与生化测定中所示的β-内酰胺酶抑制作用一致。它还抑制了质粒（CMY、FOX、MIR、DHA）和染色体编码（P99、PDC、ADC）的 C 类β-内酰胺酶和 D 类酶，包括来自 和 的碳青霉烯酶，如 OXA-48 和 OXA 酶（OXA-23/24/72/58）。QPX7728 也是许多 B 类金属β-内酰胺酶（NDM、VIM、CcrA、IMP 和 GIM，但不是 SPM 或 L1）的有效抑制剂。添加 QPX7728（4μg/ml）将大多数菌株的 MIC 降低到仅用载体对照观察到的水平，表明完全抑制了β-内酰胺酶。超广谱β-内酰胺酶抑制谱使 QPX7728 成为进一步开发的可行候选药物。
