Assay for drug discovery: Synthesis and testing of nitrocefin analogues for use as β-lactamase substrates

Ahmad Ghavami; Geneviève Labbé; Jürgen Brem; Valerie J Goodfellow; Laura Marrone; Carol A Tanner; Dustin T King; Melinda Lam; Natalie C J Strynadka; Dylan R Pillai; Stefan Siemann; James Spencer; Christopher J Schofield; Gary I Dmitrienko

doi:10.1016/j.ab.2015.06.032

Assay for drug discovery: Synthesis and testing of nitrocefin analogues for use as β-lactamase substrates

Ahmad Ghavami, Geneviève Labbé, Jürgen Brem, Valerie J Goodfellow, Laura Marrone, Carol A Tanner, Dustin T King, Melinda Lam, Natalie C J Strynadka, Dylan R Pillai, Stefan Siemann, James Spencer, Christopher J Schofield, Gary I Dmitrienko

School of Cellular and Molecular Medicine

Research output: Contribution to journal › Article (Academic Journal)

7 Citations (Scopus)

Abstract

We report on the synthesis of three nitrocefin analogues and their evaluation as substrates for the detection of β-lactamase activity. These compounds are hydrolyzed by all four Ambler classes of β-lactamases. Kinetic parameters were determined with eight different β-lactamases, including VIM-2, NDM-1, KPC-2, and SPM-1. The compounds do not inhibit the growth of clinically important antibiotic-resistant gram-negative bacteria in vitro. These chromogenic compounds have a distinct absorbance spectrum and turn purple when hydrolyzed by β-lactamases. One of these compounds, UW154, is easier to synthesize from commercial starting materials than nitrocefin and should be significantly less expensive to produce.

Original language	English
Pages (from-to)	75-7
Number of pages	3
Journal	Analytical Biochemistry
Volume	486
DOIs	https://doi.org/10.1016/j.ab.2015.06.032
Publication status	Published - 1 Oct 2015

Keywords

Biocatalysis
Cephalosporins
Chemistry Techniques, Synthetic
Drug Evaluation, Preclinical
Hydrolysis
Kinetics
beta-Lactamases

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Ghavami, A., Labbé, G., Brem, J., Goodfellow, V. J., Marrone, L., Tanner, C. A., King, D. T., Lam, M., Strynadka, N. C. J., Pillai, D. R., Siemann, S., Spencer, J., Schofield, C. J., & Dmitrienko, G. I. (2015). Assay for drug discovery: Synthesis and testing of nitrocefin analogues for use as β-lactamase substrates. Analytical Biochemistry, 486, 75-7. https://doi.org/10.1016/j.ab.2015.06.032

Ghavami, Ahmad ; Labbé, Geneviève ; Brem, Jürgen ; Goodfellow, Valerie J ; Marrone, Laura ; Tanner, Carol A ; King, Dustin T ; Lam, Melinda ; Strynadka, Natalie C J ; Pillai, Dylan R ; Siemann, Stefan ; Spencer, James ; Schofield, Christopher J ; Dmitrienko, Gary I. / Assay for drug discovery : Synthesis and testing of nitrocefin analogues for use as β-lactamase substrates. In: Analytical Biochemistry. 2015 ; Vol. 486. pp. 75-7.

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title = "Assay for drug discovery: Synthesis and testing of nitrocefin analogues for use as β-lactamase substrates",

abstract = "We report on the synthesis of three nitrocefin analogues and their evaluation as substrates for the detection of β-lactamase activity. These compounds are hydrolyzed by all four Ambler classes of β-lactamases. Kinetic parameters were determined with eight different β-lactamases, including VIM-2, NDM-1, KPC-2, and SPM-1. The compounds do not inhibit the growth of clinically important antibiotic-resistant gram-negative bacteria in vitro. These chromogenic compounds have a distinct absorbance spectrum and turn purple when hydrolyzed by β-lactamases. One of these compounds, UW154, is easier to synthesize from commercial starting materials than nitrocefin and should be significantly less expensive to produce.",

keywords = "Biocatalysis, Cephalosporins, Chemistry Techniques, Synthetic, Drug Evaluation, Preclinical, Hydrolysis, Kinetics, beta-Lactamases",

author = "Ahmad Ghavami and Genevi{\`e}ve Labb{\'e} and J{\"u}rgen Brem and Goodfellow, {Valerie J} and Laura Marrone and Tanner, {Carol A} and King, {Dustin T} and Melinda Lam and Strynadka, {Natalie C J} and Pillai, {Dylan R} and Stefan Siemann and James Spencer and Schofield, {Christopher J} and Dmitrienko, {Gary I}",

year = "2015",

month = oct,

day = "1",

doi = "10.1016/j.ab.2015.06.032",

language = "English",

volume = "486",

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journal = "Analytical Biochemistry",

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Ghavami, A, Labbé, G, Brem, J, Goodfellow, VJ, Marrone, L, Tanner, CA, King, DT, Lam, M, Strynadka, NCJ, Pillai, DR, Siemann, S, Spencer, J, Schofield, CJ & Dmitrienko, GI 2015, 'Assay for drug discovery: Synthesis and testing of nitrocefin analogues for use as β-lactamase substrates', Analytical Biochemistry, vol. 486, pp. 75-7. https://doi.org/10.1016/j.ab.2015.06.032

Assay for drug discovery : Synthesis and testing of nitrocefin analogues for use as β-lactamase substrates. / Ghavami, Ahmad; Labbé, Geneviève; Brem, Jürgen; Goodfellow, Valerie J; Marrone, Laura; Tanner, Carol A; King, Dustin T; Lam, Melinda; Strynadka, Natalie C J; Pillai, Dylan R; Siemann, Stefan; Spencer, James; Schofield, Christopher J; Dmitrienko, Gary I.

In: Analytical Biochemistry, Vol. 486, 01.10.2015, p. 75-7.

Research output: Contribution to journal › Article (Academic Journal)

TY - JOUR

T1 - Assay for drug discovery

T2 - Synthesis and testing of nitrocefin analogues for use as β-lactamase substrates

AU - Ghavami, Ahmad

AU - Labbé, Geneviève

AU - Brem, Jürgen

AU - Goodfellow, Valerie J

AU - Marrone, Laura

AU - Tanner, Carol A

AU - King, Dustin T

AU - Lam, Melinda

AU - Strynadka, Natalie C J

AU - Pillai, Dylan R

AU - Siemann, Stefan

AU - Spencer, James

AU - Schofield, Christopher J

AU - Dmitrienko, Gary I

PY - 2015/10/1

Y1 - 2015/10/1

N2 - We report on the synthesis of three nitrocefin analogues and their evaluation as substrates for the detection of β-lactamase activity. These compounds are hydrolyzed by all four Ambler classes of β-lactamases. Kinetic parameters were determined with eight different β-lactamases, including VIM-2, NDM-1, KPC-2, and SPM-1. The compounds do not inhibit the growth of clinically important antibiotic-resistant gram-negative bacteria in vitro. These chromogenic compounds have a distinct absorbance spectrum and turn purple when hydrolyzed by β-lactamases. One of these compounds, UW154, is easier to synthesize from commercial starting materials than nitrocefin and should be significantly less expensive to produce.

AB - We report on the synthesis of three nitrocefin analogues and their evaluation as substrates for the detection of β-lactamase activity. These compounds are hydrolyzed by all four Ambler classes of β-lactamases. Kinetic parameters were determined with eight different β-lactamases, including VIM-2, NDM-1, KPC-2, and SPM-1. The compounds do not inhibit the growth of clinically important antibiotic-resistant gram-negative bacteria in vitro. These chromogenic compounds have a distinct absorbance spectrum and turn purple when hydrolyzed by β-lactamases. One of these compounds, UW154, is easier to synthesize from commercial starting materials than nitrocefin and should be significantly less expensive to produce.

KW - Biocatalysis

KW - Cephalosporins

KW - Chemistry Techniques, Synthetic

KW - Drug Evaluation, Preclinical

KW - Hydrolysis

KW - Kinetics

KW - beta-Lactamases

U2 - 10.1016/j.ab.2015.06.032

DO - 10.1016/j.ab.2015.06.032

M3 - Article (Academic Journal)

C2 - 26142222

VL - 486

SP - 75

EP - 77

JO - Analytical Biochemistry

JF - Analytical Biochemistry

SN - 0003-2697

ER -