Interplay between β-lactamases and new β-lactamase inhibitors

Within-patient evolution to piperacillin/tazobactam resistance in a clinical isolate ofEscherichia colidue to IS26-mediated amplification ofblaTEM-1B

“…While this mechanism has previously been demonstrated in terms of movement of antibiotic resistance genes [21, 22], this is the first time this mechanism has been shown to cause gene amplification resulting in antibiotic resistance in a clinical isolate, be able to replicate the evolutionary event resulting in amplification in vitro and show that use of TZP either selects for or induces this phenotype. This mechanism is of concern as IS 26 has been associated with the transfer of bla NDM-1 in a recent nosocomial outbreak in Germany [42], and other carbapenemases [43] and therefore represents a risk of clinical resistance to any carbapenemase inhibitor currently in development [44] which needs to be investigated further. The method of capture of the TU used in this study can be used to investigate whether the same mechanism will result in amplification to other β-lactam/β-lactamase inhibitors, as well as to further confirm the role of TZP in the induction of excision of the TU, and therefore gene amplification.…”

Preparation and Mechanistic Studies of 2‐Substituted Bisthiazolidines by Imine Exchange

“…The proton-deuterium couplings are typically much smaller that proton-proton couplings and therefore they are not observed herein. A gradual increase of the ratio of the aldehyde protons of 2a-d (9.59 ppm, s, (v 1/2 = 0.9 Hz) and 2a (9.59 ppm, d, 3…”

“…Bisthiazolidines ( 1 ) are enantiomerically pure bicycles previously prepared in high yields (Scheme ) . Interestingly, they display activity against Metallo‐β‐Lactamases (MBLs), a diverse set of enzymes that catalyze the hydrolysis of a broad range of β‐lactam drugs including carbapenems , . These compounds have been recently characterized as cross‐class inhibitors against seven different MBLs, some of clinical relevance like NDM‐1, VIM‐2, and L1 , …”

“…[2] Interestingly, they display activity against Metallo--Lactamases (MBLs), a diverse set of enzymes that catalyze the hydrolysis of a broad range of -lactam drugs including carbapenems. [3,4] These compounds have been recently characterized as cross-class inhibitors against seven different MBLs, some of clinical relevance like NDM-1, VIM-2, and L1. [2,[5][6][7] Bicycles 1 are obtained in a tandem reaction by double condensation of L-aminothiols with two molecules of mercaptoacetaldehyde.…”

“…octane (syn 1c): Prepared in analogous route as described for 1a, starting from L-penicillamine to give 1c as a white solid: 1 H-NMR 4.98 (dd, J = 6.6, 5.4 Hz, 1H), 4.31 (t, J = 7.3 Hz, 1H),3.80 (s, 1H),3.43 (dd, J = 11.7, 6.6 Hz, 1H), 3.06 (dd, J = 11.7, 5.4 Hz, 1H), 1.89 (t, J = 8.7 Hz, 1H SH ), 2.81 (m, 2H), 1.62 (s, 3H), 1.52 (s, 3H); m.p. 89-97°C.…”