Irreversible Inhibition of Metallo‐β‐lactamase (IMP‐1) by 3‐(3‐Mercaptopropionylsulfanyl)propionic Acid Pentafluorophenyl Ester

Abstract

Widerstand ist sinnlos: Pathogene Bakterien, die Metallo‐β‐lactamasen produzieren, gelten wegen ihrer Resistenz gegen Antibiotika als große Gefahr. Nun wurde die Titelverbindung als irreversibler Inhibitor einer Metallo‐β‐lactamase (IMP‐1) identifiziert. Laut den Befunden der Röntgenstrukturanalyse (siehe Bild) bindet der Inhibitor an IMP‐1 unter Bildung einer kovalenten Amidbindung mit der Aminogruppe (Nζ) von Lys 224.

A New Approach to the Inhibition of Metallo‐β‐lactamases

“… Crystal structures of IMP‐1 metallo‐β‐lactamase and inhibitor complexes: a) 3‐(3‐mercaptopropionylsulfanyl)propionic acid (OPS; pdb accession 1vgn19); b) 2‐[5‐(1‐tetrazolylmethyl)thien‐3‐yl]‐ N ‐[2‐(mercaptomethyl)‐4‐(phenylbutyryl)glycine] (MCI; pdb 1ddk8); c) uncomplexed protein (pdb 1dd6)8); d) 2,3‐bis‐benzo[1,3]dioxol‐5‐ylmethylsuccinic acid (BDS; pdb 1jjt15). Protein main chains are color‐ramped from the N to the C termini with secondary structural elements shown in the background.…”

“…Kurosaki et al have now exploited these common features of substrate and inhibitor binding to mβls to generate a new class of irreversible thiol inhibitor 19. Irreversible inhibition of mβls by thiols is not a new observation—formation of disulfides with the Zn2 ligand Cys 221 of BcII has been demonstrated for mercaptoacetic thiol esters and postulated for thiols formed when the cephalosporin dihydrothiazine ring opens subsequent to cleavage of the β‐lactam amide bond 20.…”

“…c) Inhibition of methionine aminopeptidase by fumagillin (from reference 27). d) Inhibition of IMP‐1 metallo‐β‐lactamase by 3‐mercapto‐ and 3‐(3‐mercaptopropionylsulfanyl)propionic acid pentafluorophenyl esters (X=COSCH 2 CH 2 ) 19…”

Metallo‐β‐lactamases and Their Biomimetic Complexes

“…Simple ligands such as ethylenediaminetetraacetic acid (EDTA) and 1,10-phenanthroline (phen) have been investigated, [42,43] along with more elaborate molecules including trifluoromethyl ketones and alcohols, [44] dicarboxylic acids, [45][46][47][48] thiols, [49][50][51][52][53][54][55][56][57][58][59] sulfates, [60,61] hydroxamates, [44,62] tetrazoles, [63] sulfonamides, [64] phenazine natural products, [65][66][67] and substituted 3-mercapto-1,2,4-triazoles and N-acylated thiosemicarbazides. Simple ligands such as ethylenediaminetetraacetic acid (EDTA) and 1,10-phenanthroline (phen) have been investigated, [42,43] along with more elaborate molecules including trifluoromethyl ketones and alcohols, [44] dicarboxylic acids, [45][46][47][48] thiols, [49][50][51][52][53][54][55][56][57][58][59] sulfates, …”

An Update on the Status of Potent Inhibitors of Metallo-β-Lactamases

“…The K i values of R and S -thiomandelic acids for B. cereus enzyme were found 0.09 and 1.28 μM, respectively (Figure 3). Kurosaki at al ., [11] reported the two irreversible inhibitors 7 and 8 with K i values of 3.452 ± 0.030 μM and 0.423 ± 0.013 μM, respectively for the IMP-1 enzyme (Figure 3). …”