Zinc Chelation by a Small-Molecule Adjuvant Potentiates Meropenem Activity in Vivo against NDM-1-Producing Klebsiella pneumoniae.
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.
M. G. DeGroote Institute for Infectious Disease Research and Department of Biochemistry and Biomedical Sciences, McMaster University , Hamilton, Ontario L8N 3Z5, Canada.
Shannon B
SB
Falconer
M. G. DeGroote Institute for Infectious Disease Research and Department of Biochemistry and Biomedical Sciences, McMaster University , Hamilton, Ontario L8N 3Z5, Canada.
Sarah A
SA
Reid-Yu
M. G. DeGroote Institute for Infectious Disease Research and Department of Biochemistry and Biomedical Sciences, McMaster University , Hamilton, Ontario L8N 3Z5, Canada.
Andrew M
AM
King
M. G. DeGroote Institute for Infectious Disease Research and Department of Biochemistry and Biomedical Sciences, McMaster University , Hamilton, Ontario L8N 3Z5, Canada.
Sebastian S
SS
Gehrke
M. G. DeGroote Institute for Infectious Disease Research and Department of Biochemistry and Biomedical Sciences, McMaster University , Hamilton, Ontario L8N 3Z5, Canada.
Wenliang
W
Wang
Department of Chemistry, McMaster University , Hamilton, Ontario L8S 4M1, Canada.
James F
JF
Britten
M. G. DeGroote Institute for Infectious Disease Research and Department of Biochemistry and Biomedical Sciences, McMaster University , Hamilton, Ontario L8N 3Z5, Canada.
Brian K
BK
Coombes
M. G. DeGroote Institute for Infectious Disease Research and Department of Biochemistry and Biomedical Sciences, McMaster University , Hamilton, Ontario L8N 3Z5, Canada.
Gerard D
GD
Wright
M. G. DeGroote Institute for Infectious Disease Research and Department of Biochemistry and Biomedical Sciences, McMaster University , Hamilton, Ontario L8N 3Z5, Canada.
Eric D
ED
Brown
antibiotic adjuvant/β-lactam resistance/Klebsiella pneumoniae/zinc chelator