A γ-Lactam Siderophore Antibiotic Effective against Multidrug-Resistant Gram-Negative Bacilli

Joel A. Goldberg; Ha Nguyen; Vijay Kumar; Elizabeth J. Spencer; Denton Hoyer; Emma K. Marshall; Anna Cmolik; Margaret O'Shea; Steven H. Marshall; Andrea M. Hujer; Kristine M. Hujer; Susan D. Rudin; T. Nicholas Domitrovic; Christopher R. Bethel; Krisztina M. Papp-Wallace; Latania K. Logan; Federico Perez; Michael R. Jacobs; David Van Duin; Barry M. Kreiswirth; Robert A. Bonomo; Mark S. Plummer; Focco Van Den Akker

doi:10.1021/acs.jmedchem.0c00255

A γ-Lactam Siderophore Antibiotic Effective against Multidrug-Resistant Gram-Negative Bacilli

Joel A. Goldberg, Ha Nguyen, Vijay Kumar, Elizabeth J. Spencer, Denton Hoyer, Emma K. Marshall, Anna Cmolik, Margaret O'Shea, Steven H. Marshall, Andrea M. Hujer, Kristine M. Hujer, Susan D. Rudin, T. Nicholas Domitrovic, Christopher R. Bethel, Krisztina M. Papp-Wallace, Latania K. Logan, Federico Perez, Michael R. Jacobs, David Van Duin, Barry M. KreiswirthRobert A. Bonomo, Mark S. Plummer, Focco Van Den Akker

New Jersey Medical School (NJMS), Public Health Research Institute Center

Research output: Contribution to journal › Article › peer-review

29 Scopus citations

Abstract

Treatment of multidrug-resistant Gram-negative bacterial pathogens represents a critical clinical need. Here, we report a novel γ-lactam pyrazolidinone that targets penicillin-binding proteins (PBPs) and incorporates a siderophore moiety to facilitate uptake into the periplasm. The MIC values of γ-lactam YU253434, 1, are reported along with the finding that 1 is resistant to hydrolysis by all four classes of β-lactamases. The druglike characteristics and mouse PK data are described along with the X-ray crystal structure of 1 binding to its target PBP3.

Original language	English (US)
Pages (from-to)	5990-6002
Number of pages	13
Journal	Journal of medicinal chemistry
Volume	63
Issue number	11
DOIs	https://doi.org/10.1021/acs.jmedchem.0c00255
State	Published - Jun 11 2020

All Science Journal Classification (ASJC) codes

Molecular Medicine
Drug Discovery

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10.1021/acs.jmedchem.0c00255

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Goldberg, J. A., Nguyen, H., Kumar, V., Spencer, E. J., Hoyer, D., Marshall, E. K., Cmolik, A., O'Shea, M., Marshall, S. H., Hujer, A. M., Hujer, K. M., Rudin, S. D., Domitrovic, T. N., Bethel, C. R., Papp-Wallace, K. M., Logan, L. K., Perez, F., Jacobs, M. R., Van Duin, D., ... Van Den Akker, F. (2020). A γ-Lactam Siderophore Antibiotic Effective against Multidrug-Resistant Gram-Negative Bacilli. Journal of medicinal chemistry, 63(11), 5990-6002. https://doi.org/10.1021/acs.jmedchem.0c00255

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title = "A γ-Lactam Siderophore Antibiotic Effective against Multidrug-Resistant Gram-Negative Bacilli",

abstract = "Treatment of multidrug-resistant Gram-negative bacterial pathogens represents a critical clinical need. Here, we report a novel γ-lactam pyrazolidinone that targets penicillin-binding proteins (PBPs) and incorporates a siderophore moiety to facilitate uptake into the periplasm. The MIC values of γ-lactam YU253434, 1, are reported along with the finding that 1 is resistant to hydrolysis by all four classes of β-lactamases. The druglike characteristics and mouse PK data are described along with the X-ray crystal structure of 1 binding to its target PBP3.",

author = "Goldberg, {Joel A.} and Ha Nguyen and Vijay Kumar and Spencer, {Elizabeth J.} and Denton Hoyer and Marshall, {Emma K.} and Anna Cmolik and Margaret O'Shea and Marshall, {Steven H.} and Hujer, {Andrea M.} and Hujer, {Kristine M.} and Rudin, {Susan D.} and Domitrovic, {T. Nicholas} and Bethel, {Christopher R.} and Papp-Wallace, {Krisztina M.} and Logan, {Latania K.} and Federico Perez and Jacobs, {Michael R.} and {Van Duin}, David and Kreiswirth, {Barry M.} and Bonomo, {Robert A.} and Plummer, {Mark S.} and {Van Den Akker}, Focco",

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year = "2020",

month = jun,

day = "11",

doi = "10.1021/acs.jmedchem.0c00255",

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Goldberg, JA, Nguyen, H, Kumar, V, Spencer, EJ, Hoyer, D, Marshall, EK, Cmolik, A, O'Shea, M, Marshall, SH, Hujer, AM, Hujer, KM, Rudin, SD, Domitrovic, TN, Bethel, CR, Papp-Wallace, KM, Logan, LK, Perez, F, Jacobs, MR, Van Duin, D, Kreiswirth, BM, Bonomo, RA, Plummer, MS & Van Den Akker, F 2020, 'A γ-Lactam Siderophore Antibiotic Effective against Multidrug-Resistant Gram-Negative Bacilli', Journal of medicinal chemistry, vol. 63, no. 11, pp. 5990-6002. https://doi.org/10.1021/acs.jmedchem.0c00255

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T1 - A γ-Lactam Siderophore Antibiotic Effective against Multidrug-Resistant Gram-Negative Bacilli

AU - Goldberg, Joel A.

AU - Nguyen, Ha

AU - Kumar, Vijay

AU - Spencer, Elizabeth J.

AU - Hoyer, Denton

AU - Marshall, Emma K.

AU - Cmolik, Anna

AU - O'Shea, Margaret

AU - Marshall, Steven H.

AU - Hujer, Andrea M.

AU - Hujer, Kristine M.

AU - Rudin, Susan D.

AU - Domitrovic, T. Nicholas

AU - Bethel, Christopher R.

AU - Papp-Wallace, Krisztina M.

AU - Logan, Latania K.

AU - Perez, Federico

AU - Jacobs, Michael R.

AU - Van Duin, David

AU - Kreiswirth, Barry M.

AU - Bonomo, Robert A.

AU - Plummer, Mark S.

AU - Van Den Akker, Focco

PY - 2020/6/11

Y1 - 2020/6/11

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AB - Treatment of multidrug-resistant Gram-negative bacterial pathogens represents a critical clinical need. Here, we report a novel γ-lactam pyrazolidinone that targets penicillin-binding proteins (PBPs) and incorporates a siderophore moiety to facilitate uptake into the periplasm. The MIC values of γ-lactam YU253434, 1, are reported along with the finding that 1 is resistant to hydrolysis by all four classes of β-lactamases. The druglike characteristics and mouse PK data are described along with the X-ray crystal structure of 1 binding to its target PBP3.

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A γ-Lactam Siderophore Antibiotic Effective against Multidrug-Resistant Gram-Negative Bacilli

Abstract

All Science Journal Classification (ASJC) codes

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