Department of Bacteriology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
College of Pharmacy, Kinjo Gakuin University, Nagoya, Aichi, Japan.
mBio. 2020 Mar 17;11(2):e03144-19. doi: 10.1128/mBio.03144-19.
Production of metallo-β-lactamases (MBLs), which hydrolyze carbapenems, is a cause of carbapenem resistance in Development of effective inhibitors for MBLs is one approach to restore carbapenem efficacy in carbapenem-resistant (CRE). We report here that sulfamoyl heteroarylcarboxylic acids (SHCs) can competitively inhibit the globally spreading and clinically relevant MBLs (i.e., IMP-, NDM-, and VIM-type MBLs) at nanomolar to micromolar orders of magnitude. Addition of SHCs restored meropenem efficacy against 17/19 IMP-type and 7/14 NDM-type MBL-producing to satisfactory clinical levels. SHCs were also effective against IMP-type MBL-producing spp. and engineered strains overproducing individual minor MBLs (i.e., TMB-2, SPM-1, DIM-1, SIM-1, and KHM-1). However, SHCs were less effective against MBL-producing Combination therapy with meropenem and SHCs successfully cured mice infected with IMP-1-producing and dually NDM-1/VIM-1-producing clinical isolates. X-ray crystallographic analyses revealed the inhibition mode of SHCs against MBLs; the sulfamoyl group of SHCs coordinated to two zinc ions, and the carboxylate group coordinated to one zinc ion and bound to positively charged amino acids Lys224/Arg228 conserved in MBLs. Preclinical testing revealed that the SHCs showed low toxicity in cell lines and mice and high stability in human liver microsomes. Our results indicate that SHCs are promising lead compounds for inhibitors of MBLs to combat MBL-producing CRE. Carbapenem antibiotics are the last resort for control of severe infectious diseases, bloodstream infections, and pneumonia caused by Gram-negative bacteria, including However, carbapenem-resistant (CRE) strains have spread globally and are a critical concern in clinical settings because CRE infections are recognized as a leading cause of increased mortality among hospitalized patients. Most CRE produce certain kinds of serine carbapenemases (e.g., KPC- and GES-type β-lactamases) or metallo-β-lactamases (MBLs), which can hydrolyze carbapenems. Although effective MBL inhibitors are expected to restore carbapenem efficacy against MBL-producing CRE, no MBL inhibitor is currently clinically available. Here, we synthesized 2,5-diethyl-1-methyl-4-sulfamoylpyrrole-3-carboxylic acid (SPC), which is a potent inhibitor of MBLs. SPC is a remarkable lead compound for clinically useful MBL inhibitors and can potentially provide a considerable benefit to patients receiving treatment for lethal infectious diseases caused by MBL-producing CRE.
金属β-内酰胺酶（MBLs）能够水解碳青霉烯类抗生素，是导致碳青霉烯类抗生素耐药性的原因之一。开发有效的 MBLs 抑制剂是恢复碳青霉烯类抗生素对产碳青霉烯酶肠杆菌科（CRE）疗效的一种方法。我们在此报告，磺酰胺杂芳基羧酸（SHC）可以在纳摩尔到微摩尔的数量级上竞争性抑制全球传播和临床相关的 MBLs（即 IMP、NDM 和 VIM 型 MBLs）。添加 SHC 可将美罗培南对 17/19 种 IMP 型和 7/14 种 NDM 型 MBL 产生菌的疗效恢复至令人满意的临床水平。SHC 对产 IMP 型 MBL 的 属和过表达单个次要 MBL（即 TMB-2、SPM-1、DIM-1、SIM-1 和 KHM-1）的工程 菌株也有效。然而，SHC 对产 MBL 的 属的疗效较低。美罗培南与 SHC 的联合治疗成功治愈了感染 IMP-1 产生菌和双重 NDM-1/VIM-1 产生菌临床分离株的小鼠。X 射线晶体学分析揭示了 SHC 对 MBL 的抑制模式；SHC 的磺酰胺基与两个锌离子配位，羧基与一个锌离子配位，并与 MBL 中保守的带正电荷的氨基酸 Lys224/Arg228 结合。临床前测试表明，SHC 在细胞系和小鼠中具有低毒性，在人肝微粒体中具有高稳定性。我们的结果表明，SHC 是一种有前途的 MBL 抑制剂先导化合物，可用于治疗产 MBL 的 CRE。碳青霉烯类抗生素是控制革兰氏阴性菌引起的严重感染性疾病、血流感染和肺炎的最后手段，包括 然而，产碳青霉烯酶的 （CRE）菌株已在全球范围内传播，并且在临床环境中是一个关键关注点，因为 CRE 感染被认为是住院患者死亡率增加的主要原因。大多数 CRE 产生某些种类的丝氨酸碳青霉烯酶（例如，KPC-和 GES 型β-内酰胺酶）或金属β-内酰胺酶（MBLs），可水解碳青霉烯类抗生素。尽管有效的 MBL 抑制剂有望恢复对产 MBL 的 CRE 的碳青霉烯类抗生素疗效，但目前临床上尚无 MBL 抑制剂。在这里，我们合成了 2,5-二乙基-1-甲基-4-磺酰胺基吡咯-3-羧酸（SPC），它是一种有效的 MBL 抑制剂。SPC 是一种很有前途的临床有效 MBL 抑制剂的先导化合物，可能会为接受治疗产 MBL 的 CRE 引起的致命性传染病的患者带来显著的益处。
