Zinc Chelation by a Small-Molecule Adjuvant Potentiates Meropenem Activity in Vivo against NDM-1-Producing Klebsiella pneumoniae

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• 作者：Shannon B. Falconer ; Sarah A. Reid-Yu ; Andrew M. King ; Sebastian S. Gehrke ; Wenliang Wang ; James F. Britten ; Brian K. Coombes ; Gerard D. Wright ; Eric D. Brown
• 刊名：ACS Infectious Diseases
• 出版年：2015
• 出版时间：November 13, 2015
• 年：2015
• 卷：1
• 期：11
• 页码：533-543
• 全文大小：534K
• ISSN：2373-8227

文摘

The widespread emergence of antibiotic drug resistance has resulted in a worldwide healthcare crisis. In particular, the extensive use of β-lactams, a highly effective class of antibiotics, has been a driver for pervasive β-lactam resistance. Among the most important resistance determinants are the metallo-β-lactamases (MBL), which are zinc-requiring enzymes that inactivate nearly all classes of β-lactams, including the last-resort carbapenem antibiotics. The urgent need for new compounds targeting MBL resistance mechanisms has been widely acknowledged; however, the development of certain types of compounds—namely metal chelators—is actively avoided due to host toxicity concerns. The work herein reports the identification of a series of zinc-selective spiro-indoline-thiadiazole analogues that, in vitro, potentiate β-lactam antibiotics against an MBL-carrying pathogen by withholding zinc availability. This study demonstrates the ability of one such analogue to inhibit NDM-1 in vitro and, using a mouse model of infection, shows that combination treatment of the respective analogue with meropenem results in a significant decrease in bacterial burden in contrast to animals that received antibiotic treatment alone. These results support the therapeutic potential of these chelators in overcoming antibiotic resistance.