Challenges in the Development of a Thiol-Based Broad-Spectrum Inhibitor for Metallo-β-Lactamases

Pathogens, expressing metallo-β-lactamases (MBLs), become resistant against most β-lactam antibiotics. Besides the dragging search for new antibiotics, development of MBL inhibitors would be an alternative weapon against resistant bacterial pathogens. Inhibition of resistance enzymes could restore the antibacterial activity of β-lactams. Various approaches to MBL inhibitors are described; among others, the promising motif of a zinc coordinating thiol moiety is very popular. Nevertheless, since the first report of a thiol-based MBL inhibitor (thiomandelic acid) in 2001, no steps in development of thiol based MBL inhibitors were reported that go beyond clinical isolate testing. In this study, we report on the synthesis and biochemical characterization of thiol-based MBL inhibitors and highlight the challenges behind the development of thiol-based compounds, which exhibit good in vitro activity toward a broad spectrum of MBLs, selectivity against human off-targets, and reasonable activity against clinical isolates

Can Pearlite form Outside of the Hultgren Extrapolation of the Ae3 and Acm Phase Boundaries?

It is usually assumed that ferrous pearlite can form only when the average austenite carbon concentration C lies between the extrapolated Ae3 (γ/α) and Acm (γ/θ) phase boundaries (the “Hultgren extrapolation”). This “mutual supersaturation” criterion for cooperative lamellar nucleation and growth is critically examined from a historical perspective and in light of recent experiments on coarse-grained hypoeutectoid steels which show pearlite formation outside the Hultgren extrapolation. This criterion, at least as interpreted in terms of the average austenite composition, is shown to be unnecessarily restrictive. The carbon fluxes evaluated from Brandt’s solution are sufficient to allow pearlite growth both inside and outside the Hultgren Extrapolation. As for the feasibility of the nucleation events leading to pearlite, the only criterion is that there are some local regions of austenite inside the Hultgren Extrapolation, even if the average austenite composition is outside.MMA and CC acknowledge financial support from Spanish Ministerio de Ciencia e Innovación in the form of a Coordinate Project (ENE2009-13766-C04-01). REH acknowledges support from the U.S. Department of Energy (contract DE-AC52-06NA25396).Peer Reviewe