Bisthiazolidines: a substrate-mimicking scaffold as an inhibitor of the NDM-1 carbapenemase

GONZALEZ, MARIANO M.; KOSMOPOULOU, MAGDA; MOJICA, MARIA; CASTILLO, VALERIE; HINCHLIFFE, PHILIP; PETTINATI, ILARIA; BREM, JÜRGEN; SCHOFIELD, CHRISTOPHER; MAHLER, GRACIELA; BONOMO, ROBERT; LLARRULL, LETICIA I.; SPENCER, JAMES; VILA, ALEJANDRO J.

ACS Infectious Diseases

ACS Publications

Año: 2015 vol. 1 p. 544 - 554

Pathogenic Gram-negative bacteria resistant to almost all beta-lactam antibiotics are a major public health threat. Zn(II)-dependent or metallo-beta-lactamases (MBLs) produced by these bacteria inactivate most beta-lactam antibiotics, including the carbapenems which are "last line therapies" for life threatening Gram-negative infections. NDM-1 is a carbapenemase belonging to the MBL family that is rapidly spreading worldwide. Regrettably, inhibitors of MBLs are not yet developed. Here we present the bisthiazolidine (BTZ) scaffold as a structure with some features of beta-lactam substrates, which can be modified with metal binding groups to target the MBL active site. Inspired by known interactions of MBLs with beta-lactams, we designed four BTZs which behave as in vitro NDM-1 inhibitors with Ki values in the low micromolar range (7 ± 1 to 19 ± 3 uM). NMR spectroscopy demonstrated that they inhibit hydrolysis of imipenem in NDM-1 producing Escherichia coli. In vitro time-kill cell based assays against a variety of bacterial strains harboring blaNDM-1 including Acinetobacter baumannii show that the compounds restor the antibacterial activity of imipenem. A crystal structure of the most potent heterocycle (L-CS319) in complex with NDM-1 at 1.9 Å resolution identified both structural determinants for inhibitor binding and opportunities for further improvements in potency.