Linciano Pasquale, Gianquinto Eleonora, Montanari Martina, Maso Lorenzo, Bellio Pierangelo, Cebrián-Sastre Esmeralda, Celenza Giuseppe, Blázquez Jesús, Cendron Laura, Spyrakis Francesca, Tondi Donatella
Department of Life Sciences, University of Modena and Reggio Emilia, Via G. Campi 103, 41125 Modena, Italy.
Department of Drug Science and Technology, University of Turin, Via P. Giuria 9, 10125 Turin, Italy.
Pharmaceuticals (Basel). 2020 Mar 24;13(3):52. doi: 10.3390/ph13030052.
The emergence of bacteria that co-express serine- and metallo- carbapenemases is a threat to the efficacy of the available -lactam antibiotic armamentarium. The 4-amino-1,2,4-triazole-3-thione scaffold has been selected as the starting chemical moiety in the design of a small library of -Lactamase inhibitors (BLIs) with extended activity profiles. The synthesised compounds have been validated in vitro against class A serine Lactamase (SBLs) KPC-2 and class B1 metallo Lactamases (MBLs) VIM-1 and IMP-1. Of the synthesised derivatives, four compounds showed cross-class micromolar inhibition potency and therefore underwent analyses to elucidate their binding mode within the catalytic pockets of serine- and metallo-BLs. Moreover, several members of the synthesised library have been evaluated, in combination with meropenem (MEM), against clinical strains that overexpress BLs for their ability to synergise carbapenems.
共表达丝氨酸碳青霉烯酶和金属碳青霉烯酶的细菌的出现，对现有β-内酰胺抗生素库的疗效构成威胁。4-氨基-1,2,4-三唑-3-硫酮支架已被选为设计具有扩展活性谱的β-内酰胺酶抑制剂（BLI）小文库的起始化学部分。合成的化合物已在体外针对A类丝氨酸β-内酰胺酶（SBL）KPC-2和B1类金属β-内酰胺酶（MBL）VIM-1和IMP-1进行了验证。在合成的衍生物中，有四种化合物表现出跨类微摩尔抑制效力，因此进行了分析以阐明它们在丝氨酸和金属β-内酰胺酶催化口袋内的结合模式。此外，已对合成文库的几个成员与美罗培南（MEM）联合进行评估，以检测它们针对过表达β-内酰胺酶的临床菌株增强碳青霉烯类药物疗效的能力。
