2014
DOI: 10.1021/bi500887n
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Biochemical and Structural Analysis of Inhibitors Targeting the ADC-7 Cephalosporinase of Acinetobacter baumannii

Abstract: β-Lactam resistance in Acinetobacter baumannii presents one of the greatest challenges to contemporary antimicrobial chemotherapy. Much of this resistance to cephalosporins derives from the expression of the class C β-lactamase enzymes, known as Acinetobacter-derived cephalosporinases (ADCs). Currently, β-lactamase inhibitors are structurally similar to β-lactam substrates and are not effective inactivators of this class C cephalosporinase. Herein, two boronic acid transition state inhibitors (BATSIs S02030 an… Show more

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Cited by 36 publications
(80 citation statements)
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“…In addition, at position R2, a substituted phenyl or triazole resulted in lower IC 50 s. Finally, the change of amide into sulfonamide or urea was beneficial (26), while the thiourea was not active. We also discovered that against SHV-1 ␤-lactamase, and more strikingly against KPC-2, compound 2b exhibited a time-dependent inactivation, a behavior that was previously observed for other ␤-lactamases when inactivated with BATSIs (19,24). By identifying common features of these new BATSIs, novel SAR studies to target KPC-2 and other clinically important ␤-lactamases can be performed with the aim of determining key amino acid residues in the catalytic pocket that contribute to molecular recognition.…”
Section: Resultssupporting
confidence: 74%
See 1 more Smart Citation
“…In addition, at position R2, a substituted phenyl or triazole resulted in lower IC 50 s. Finally, the change of amide into sulfonamide or urea was beneficial (26), while the thiourea was not active. We also discovered that against SHV-1 ␤-lactamase, and more strikingly against KPC-2, compound 2b exhibited a time-dependent inactivation, a behavior that was previously observed for other ␤-lactamases when inactivated with BATSIs (19,24). By identifying common features of these new BATSIs, novel SAR studies to target KPC-2 and other clinically important ␤-lactamases can be performed with the aim of determining key amino acid residues in the catalytic pocket that contribute to molecular recognition.…”
Section: Resultssupporting
confidence: 74%
“…This finding was consistent with the crystal structure of 2b (S02030) with the class C ␤-lactamase. ADC-7 revealed multiple conformations of the compound in the active site as well (24). Based on the possible conformations of 2b into the active site of ADC-7, a similar binding mode with KPC-2 and SHV-1 enzymes was chosen (Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Previously, the structure of S02030 bound to the class C ADC-7 ␤-lactamase from A. baumannii was determined (17), allowing us now to compare the modes of binding of S02030 to the two class A ␤-lactamases determined herein. The ADC-7-S02030 complex structure (PDB code 4U0X) was comprised of 4 independently refined ADC-7 molecules in the asymmetric unit, each having an S02030 molecule bound.…”
Section: Resultsmentioning
confidence: 99%
“…Recently, the BATSI S02030 ( Fig. 1) was found to inhibit ADC-7 ␤-lactamase from Acinetobacter baumannii by forming a transition state boron-mediated bond with the catalytic serine (17). We have extended the structural investigations of S02030 and observed that it readily inhibits SHV-1 and KPC-2 ␤-lactamases (see also the companion article by Rojas et al [18]).…”
mentioning
confidence: 83%
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