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.
Falconer SB, Reid-Yu SA, King AM, Gehrke SS, Wang W, Britten JF, Coombes BK, Wright GD, Brown ED.
ACS Infect Dis. 2015 Nov 13;1(11):533-43. doi: 10.1021/acsinfecdis.5b00033.