TY - JOUR
T1 - Small Molecule Carboxylates Inhibit Metallo-β-lactamases and Resensitize Carbapenem-Resistant Bacteria to Meropenem
AU - Tehrani, Kamaleddin H.M.E.
AU - Brüchle, Nora C.
AU - Wade, Nicola
AU - Mashayekhi, Vida
AU - Pesce, Diego
AU - van Haren, Matthijs J.
AU - Martin, Nathaniel I.
PY - 2020/6/12
Y1 - 2020/6/12
N2 - In the search for new inhibitors of bacterial metallo-β-lactamases (MBLs), a series of commonly used small molecule carboxylic acid derivatives were evaluated for their ability to inhibit New Delhi metallo-β-lactamase (NDM)-, Verona integron-encoded metallo-β-lactamase (VIM)-, and imipenemase (IMP)-type enzymes. Nitrilotriacetic acid (3) and N-(phosphonomethyl)iminodiacetic acid (5) showed promising activity especially against NDM-1 and VIM-2 with IC50 values in the low-to-sub μM range. Binding assays using isothermal titration calorimetry reveal that 3 and 5 bind zinc with high affinity with dissociation constant (Kd) values of 121 and 56 nM, respectively. The in vitro biological activity of 3 and 5 against E. coli expressing NDM-1 was evaluated in checkerboard format, demonstrating a strong synergistic relationship for both compounds when combined with Meropenem. Compounds 3 and 5 were then tested against 35 pathogenic strains expressing MBLs of the NDM, VIM, or IMP classes. Notably, when combined with Meropenem, compounds 3 and 5 were found to lower the minimum inhibitory concentration (MIC) of Meropenem up to 128-fold against strains producing NDM- and VIM-type enzymes.
AB - In the search for new inhibitors of bacterial metallo-β-lactamases (MBLs), a series of commonly used small molecule carboxylic acid derivatives were evaluated for their ability to inhibit New Delhi metallo-β-lactamase (NDM)-, Verona integron-encoded metallo-β-lactamase (VIM)-, and imipenemase (IMP)-type enzymes. Nitrilotriacetic acid (3) and N-(phosphonomethyl)iminodiacetic acid (5) showed promising activity especially against NDM-1 and VIM-2 with IC50 values in the low-to-sub μM range. Binding assays using isothermal titration calorimetry reveal that 3 and 5 bind zinc with high affinity with dissociation constant (Kd) values of 121 and 56 nM, respectively. The in vitro biological activity of 3 and 5 against E. coli expressing NDM-1 was evaluated in checkerboard format, demonstrating a strong synergistic relationship for both compounds when combined with Meropenem. Compounds 3 and 5 were then tested against 35 pathogenic strains expressing MBLs of the NDM, VIM, or IMP classes. Notably, when combined with Meropenem, compounds 3 and 5 were found to lower the minimum inhibitory concentration (MIC) of Meropenem up to 128-fold against strains producing NDM- and VIM-type enzymes.
KW - isothermal titration calorimetry
KW - MBL inhibitors
KW - NDM-1
KW - synergy
KW - zinc binding
U2 - 10.1021/acsinfecdis.9b00459
DO - 10.1021/acsinfecdis.9b00459
M3 - Article
C2 - 32227874
AN - SCOPUS:85086419367
SN - 2373-8227
VL - 6
SP - 1366
EP - 1371
JO - ACS Infectious Diseases
JF - ACS Infectious Diseases
IS - 6
ER -