Discovery of a new class of non-β-lactam inhibitors of penicillin-binding proteins with gram-positive antibacterial activity

Peter I. O'Daniel; Zhihong Peng; Hualiang Pi; Sebastian A. Testero; Derong Ding; Edward Spink; Erika Leemans; Marc A. Boudreau; Takao Yamaguchi; Valerie A. Schroeder; William R. Wolter; Leticia I. Llarrull; Wei Song; Elena Lastochkin; Malika Kumarasiri; Nuno T. Antunes; Mana Espahbodi; Katerina Lichtenwalter; Mark A. Suckow; Sergei Vakulenko; Shahriar Mobashery; Mayland Chang

doi:10.1021/ja500053x

Discovery of a new class of non-β-lactam inhibitors of penicillin-binding proteins with gram-positive antibacterial activity

Peter I. O'Daniel
, Zhihong Peng
, Hualiang Pi
, Sebastian A. Testero
, Derong Ding
, Edward Spink
, Erika Leemans
, Marc A. Boudreau
, Takao Yamaguchi
, Valerie A. Schroeder
, William R. Wolter
, Leticia I. Llarrull
, Wei Song
, Elena Lastochkin
, Malika Kumarasiri
, Nuno T. Antunes
, Mana Espahbodi
, Katerina Lichtenwalter
, Mark A. Suckow
, Sergei Vakulenko

Shahriar Mobashery, Mayland Chang

Administration (AHS)

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

127 Scopus citations

Abstract

Infections caused by hard-to-treat methicillin-resistant Staphylococcus aureus (MRSA) are a serious global public-health concern, as MRSA has become broadly resistant to many classes of antibiotics. We disclose herein the discovery of a new class of non-β-lactam antibiotics, the oxadiazoles, which inhibit penicillin-binding protein 2a (PBP2a) of MRSA. The oxadiazoles show bactericidal activity against vancomycin-and linezolid-resistant MRSA and other Gram-positive bacterial strains, in vivo efficacy in a mouse model of infection, and have 100% oral bioavailability.

Original language	English (US)
Pages (from-to)	3664-3672
Number of pages	9
Journal	Journal of the American Chemical Society
Volume	136
Issue number	9
DOIs	https://doi.org/10.1021/ja500053x
State	Published - Mar 5 2014

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This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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10.1021/ja500053x

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O'Daniel, P. I., Peng, Z., Pi, H., Testero, S. A., Ding, D., Spink, E., Leemans, E., Boudreau, M. A., Yamaguchi, T., Schroeder, V. A., Wolter, W. R., Llarrull, L. I., Song, W., Lastochkin, E., Kumarasiri, M., Antunes, N. T., Espahbodi, M., Lichtenwalter, K., Suckow, M. A., ... Chang, M. (2014). Discovery of a new class of non-β-lactam inhibitors of penicillin-binding proteins with gram-positive antibacterial activity. Journal of the American Chemical Society, 136(9), 3664-3672. https://doi.org/10.1021/ja500053x

O'Daniel, PI, Peng, Z, Pi, H, Testero, SA, Ding, D, Spink, E, Leemans, E, Boudreau, MA, Yamaguchi, T, Schroeder, VA, Wolter, WR, Llarrull, LI, Song, W, Lastochkin, E, Kumarasiri, M, Antunes, NT, Espahbodi, M, Lichtenwalter, K, Suckow, MA, Vakulenko, S, Mobashery, S & Chang, M 2014, 'Discovery of a new class of non-β-lactam inhibitors of penicillin-binding proteins with gram-positive antibacterial activity', Journal of the American Chemical Society, vol. 136, no. 9, pp. 3664-3672. https://doi.org/10.1021/ja500053x

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title = "Discovery of a new class of non-β-lactam inhibitors of penicillin-binding proteins with gram-positive antibacterial activity",

abstract = "Infections caused by hard-to-treat methicillin-resistant Staphylococcus aureus (MRSA) are a serious global public-health concern, as MRSA has become broadly resistant to many classes of antibiotics. We disclose herein the discovery of a new class of non-β-lactam antibiotics, the oxadiazoles, which inhibit penicillin-binding protein 2a (PBP2a) of MRSA. The oxadiazoles show bactericidal activity against vancomycin-and linezolid-resistant MRSA and other Gram-positive bacterial strains, in vivo efficacy in a mouse model of infection, and have 100\% oral bioavailability.",

author = "O'Daniel, \{Peter I.\} and Zhihong Peng and Hualiang Pi and Testero, \{Sebastian A.\} and Derong Ding and Edward Spink and Erika Leemans and Boudreau, \{Marc A.\} and Takao Yamaguchi and Schroeder, \{Valerie A.\} and Wolter, \{William R.\} and Llarrull, \{Leticia I.\} and Wei Song and Elena Lastochkin and Malika Kumarasiri and Antunes, \{Nuno T.\} and Mana Espahbodi and Katerina Lichtenwalter and Suckow, \{Mark A.\} and Sergei Vakulenko and Shahriar Mobashery and Mayland Chang",

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AU - O'Daniel, Peter I.

AU - Peng, Zhihong

AU - Pi, Hualiang

AU - Testero, Sebastian A.

AU - Ding, Derong

AU - Spink, Edward

AU - Leemans, Erika

AU - Boudreau, Marc A.

AU - Yamaguchi, Takao

AU - Schroeder, Valerie A.

AU - Wolter, William R.

AU - Llarrull, Leticia I.

AU - Song, Wei

AU - Lastochkin, Elena

AU - Kumarasiri, Malika

AU - Antunes, Nuno T.

AU - Espahbodi, Mana

AU - Lichtenwalter, Katerina

AU - Suckow, Mark A.

AU - Vakulenko, Sergei

AU - Mobashery, Shahriar

AU - Chang, Mayland

PY - 2014/3/5

Y1 - 2014/3/5

N2 - Infections caused by hard-to-treat methicillin-resistant Staphylococcus aureus (MRSA) are a serious global public-health concern, as MRSA has become broadly resistant to many classes of antibiotics. We disclose herein the discovery of a new class of non-β-lactam antibiotics, the oxadiazoles, which inhibit penicillin-binding protein 2a (PBP2a) of MRSA. The oxadiazoles show bactericidal activity against vancomycin-and linezolid-resistant MRSA and other Gram-positive bacterial strains, in vivo efficacy in a mouse model of infection, and have 100% oral bioavailability.

AB - Infections caused by hard-to-treat methicillin-resistant Staphylococcus aureus (MRSA) are a serious global public-health concern, as MRSA has become broadly resistant to many classes of antibiotics. We disclose herein the discovery of a new class of non-β-lactam antibiotics, the oxadiazoles, which inhibit penicillin-binding protein 2a (PBP2a) of MRSA. The oxadiazoles show bactericidal activity against vancomycin-and linezolid-resistant MRSA and other Gram-positive bacterial strains, in vivo efficacy in a mouse model of infection, and have 100% oral bioavailability.

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SN - 0002-7863

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SP - 3664

EP - 3672

JO - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

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ER -

Discovery of a new class of non-β-lactam inhibitors of penicillin-binding proteins with gram-positive antibacterial activity

Abstract

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