Journal
ACS INFECTIOUS DISEASES
Volume 1, Issue 11, Pages 533-543Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsinfecdis.5b00033
Keywords
antibiotic adjuvant; beta-lactam resistance; Klebsiella pneumoniae; zinc chelator
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Funding
- Canadian Institutes of Health Research (CIHR) [MOP-81330]
- Canada Research Chairs program
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The widespread emergence of antibiotic drug resistance has resulted in a worldwide healthcare crisis. In particular, the extensive use of beta-lactams, a highly effective class of antibiotics, has been a driver for pervasive beta-lactam resistance. Among the most important resistance determinants are the metallo-beta-lactamases (MBL), which are zinc-requiring enzymes that inactivate nearly all classes of beta-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 beta-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.
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