Sulfamoyl Heteroarylcarboxylic Acids as Promising Metallo-β-Lactamase Inhibitors for Controlling Bacterial Carbapenem Resistance
Sulfamoyl Heteroarylcarboxylic Acids as Promising Metallo-β-Lactamase Inhibitors for Controlling Bacterial Carbapenem Resistance
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氨磺酰杂芳基羧酸作为有前途的金属-β-内酰胺酶抑制剂，用于控制细菌碳青霉烯类耐药性
DOI：
10.1128/mbio.03144-19
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发表时间：
2020
期刊：
影响因子：
6.4
通讯作者：
Arakawa Yoshichika
中科院分区：
文献类型：
--
作者：
Wachino Jun-ichi;Jin Wanchun;Kimura Kouji;Kurosaki Hiromasa;Sato Ayato;Arakawa Yoshichika
金属-β-内酰胺酶(MBLS)的产生是导致肠杆菌科细菌对碳青霉烯类抗生素耐药的原因之一。开发有效的MBLS抑制剂是恢复碳青霉烯类耐药肠杆菌科细菌(CRE)碳青霉烯疗效的方法之一。我们在此报道，磺胺甲酰基异芳基羧酸(SHCS)可以在纳摩尔到微摩尔数量级竞争性地抑制全球传播的和临床相关的MBLs(即IMP-型、NDM-型和VIM-型MBL)。SHCS的加入使美罗培南对17/19 IMP型和7/14 NDM型产MBL肠杆菌的疗效恢复到令人满意的临床水平。对IMP型产MBL不动杆菌也有较好的抗菌活性。和过量生产单个小MB的工程化大肠杆菌菌株(即TMB-2、SPM-1、DIM-1、SIM-1和KHM-1)。然而，SHCS对产MBL的铜绿假单胞菌的疗效较差。美罗培南和SHCS的联合治疗成功治愈了感染产生IMP-1的大肠杆菌和双重产生NDM-1/VIM-1的肺炎克雷伯菌临床分离株的小鼠。X-射线单晶分析揭示了SHCS对MBLS的抑制模式：SMCS的磺酰基与两个锌离子配位，羧酸基与一个锌离子配位，并与MBLS中保守的带正电荷的氨基酸Lys224/Arg228结合。临床前试验表明，SHCS对细胞系和小鼠的毒性低，对人肝微粒体的稳定性高。我们的结果表明，SHC是很有前景的MBLS抑制剂的先导化合物，以对抗产生MBL的CRE。重要的是，碳青霉烯类抗生素是控制严重感染性疾病、血液感染和革兰氏阴性菌肺炎的最后手段，包括肠杆菌科细菌。然而，耐碳青霉烯类肠杆菌科(CRE)菌株已在全球传播，并在临床环境中引起严重关注，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产生某些类型的丝氨酸碳青霉烯酶(如KpC和GES型β-内酰胺酶)或金属-β-内酰胺酶(MBLS)，它们可以水解碳青霉烯类抗生素。尽管有效的MBL抑制剂有望恢复碳青霉烯类药物对产生MBL的CRE的疗效，但目前还没有MBL抑制剂可用于临床。在这里，我们合成了2，5-diethyl-1-methyl-4-sulfamoylpyrrole-3-carboxylic酸(Spc)，它是一种有效的MBLS抑制剂。SPC是临床上有用的MBL抑制剂的重要先导化合物，并可能为接受由产生MBL的CRE引起的致命传染病治疗的患者提供相当大的好处。
Production of metallo-β-lactamases (MBLs), which hydrolyze carbapenems, is a cause of carbapenem resistance inEnterobacteriaceae. Development of effective inhibitors for MBLs is one approach to restore carbapenem efficacy in carbapenem-resistantEnterobacteriaceae(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-producingEnterobacteriaceaeto satisfactory clinical levels. SHCs were also effective against IMP-type MBL-producing Acinetobacter spp. and engineered Escherichia coli 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 Pseudomonas aeruginosa. Combination therapy with meropenem and SHCs successfully cured mice infected with IMP-1-producing E. coli and dually NDM-1/VIM-1-producing Klebsiella pneumoniae 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.IMPORTANCECarbapenem antibiotics are the last resort for control of severe infectious diseases, bloodstream infections, and pneumonia caused by Gram-negative bacteria, includingEnterobacteriaceae. However, carbapenem-resistantEnterobacteriaceae(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.