Differential active site requirements for NDM-1 β-lactamase hydrolysis of carbapenem versus penicillin and cephalosporin antibiotics

Sun, Zhizeng; Hu, Liya; Sankaran, Banumathi; Prasad, B. V.  Venkataram; Palzkill, Timothy

doi:10.1038/s41467-018-06839-1

Title: Differential active site requirements for NDM-1 β-lactamase hydrolysis of carbapenem versus penicillin and cephalosporin antibiotics

Journal Article · Tue Oct 30 00:00:00 EDT 2018 · Nature Communications

DOI:https://doi.org/10.1038/s41467-018-06839-1· OSTI ID:1546626

^[1];

^[1]; Sankaran, Banumathi ^[2]; Prasad, B. V. Venkataram ^[1]; Palzkill, Timothy ^[1]

Baylor College of Medicine, Houston, TX (United States)
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

New Delhi metallo-β-lactamase-1 exhibits a broad substrate profile for hydrolysis of the penicillin, cephalosporin and 'last resort' carbapenems, and thus confers bacterial resistance to nearly all β-lactam antibiotics. Here we address whether the high catalytic efficiency for hydrolysis of these diverse substrates is reflected by similar sequence and structural requirements for catalysis, i.e., whether the same catalytic machinery is used to achieve hydrolysis of each class. Deep sequencing of randomized single codon mutation libraries that were selected for resistance to representative antibiotics reveal stringent sequence requirements for carbapenem versus penicillin or cephalosporin hydrolysis. Further, the residue positions required for hydrolysis of penicillins and cephalosporins are a subset of those required for carbapenem hydrolysis. Thus, while a common core of residues is used for catalysis of all substrates, carbapenem hydrolysis requires an additional set of residues to achieve catalytic efficiency comparable to that for penicillins and cephalosporins.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1546626

Journal Information:: Nature Communications, Vol. 9, Issue 1; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 47 works

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