A lipoglycopeptide antibiotic for Gram-positive biofilm-related infections

Mark A.T. Blaskovich; Karl A. Hansford; Mark S. Butler; Soumya Ramu; Angela M. Kavanagh; Angie M. Jarrad; Anggia Prasetyoputri; Miranda E. Pitt; Johnny X. Huang; Fredrik Lindahl; Zyta M. Ziora; Tanya Bradford; Craig Muldoon; Premraj Rajaratnam; Ruby Pelingon; David J. Edwards; Bing Zhang; Maite Amado; Alysha G. Elliott; Johannes Zuegg; Lachlan Coin; Anne Kathrin Woischnig; Nina Khanna; Elena Breidenstein; Anna Stincone; Clive Mason; Nawaz Khan; Hye Kyung Cho; Melissa J. Karau; Kerryl E. Greenwood-Quaintance; Robin Patel; Mandy Wootton; Meagan L. James; Melanie L. Hutton; Dena Lyras; Abiodun D. Ogunniyi; Layla K. Mahdi; Darren J. Trott; Xiaoqian Wu; Samantha Niles; Kim Lewis; Jordan R. Smith; Katie E. Barber; Juwon Yim; Seth Alan Rice; Michael J. Rybak; Chad R. Ishmael; Kellyn R. Hori; Nicholas M. Bernthal; Kevin P. Francis; Jason A. Roberts; David L. Paterson; Matthew A. Cooper

doi:10.1126/scitranslmed.abj238

A lipoglycopeptide antibiotic for Gram-positive biofilm-related infections

Mark A.T. Blaskovich, Karl A. Hansford, Mark S. Butler, Soumya Ramu, Angela M. Kavanagh, Angie M. Jarrad, Anggia Prasetyoputri, Miranda E. Pitt, Johnny X. Huang, Fredrik Lindahl, Zyta M. Ziora, Tanya Bradford, Craig Muldoon, Premraj Rajaratnam, Ruby Pelingon, David J. Edwards, Bing Zhang, Maite Amado, Alysha G. Elliott, Johannes ZueggLachlan Coin, Anne Kathrin Woischnig, Nina Khanna, Elena Breidenstein, Anna Stincone, Clive Mason, Nawaz Khan, Hye Kyung Cho, Melissa J. Karau, Kerryl E. Greenwood-Quaintance, Robin Patel, Mandy Wootton, Meagan L. James, Melanie L. Hutton, Dena Lyras, Abiodun D. Ogunniyi, Layla K. Mahdi, Darren J. Trott, Xiaoqian Wu, Samantha Niles, Kim Lewis, Jordan R. Smith, Katie E. Barber, Juwon Yim, Seth Alan Rice, Michael J. Rybak, Chad R. Ishmael, Kellyn R. Hori, Nicholas M. Bernthal, Kevin P. Francis, Jason A. Roberts, David L. Paterson, Matthew A. Cooper

Laboratory Medicine and Pathology

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

Abstract

Drug-resistant Gram-positive bacterial infections are still a substantial burden on the public health system, with two bacteria (Staphylococcus aureus and Streptococcus pneumoniae) accounting for over 1.5 million drug-resistant infections in the United States alone in 2017. In 2019, 250,000 deaths were attributed to these pathogens globally. We have developed a preclinical glycopeptide antibiotic, MCC5145, that has excellent potency (MIC90 ≤ 0.06 μg/ml) against hundreds of isolates of methicillin-resistant S. aureus (MRSA) and other Gram-positive bacteria, with a greater than 1000-fold margin over mammalian cell cytotoxicity values. The antibiotic has therapeutic in vivo efficacy when dosed subcutaneously in multiple murine models of established bacterial infections, including thigh infection with MRSA and blood septicemia with S. pneumoniae, as well as when dosed orally in an antibiotic-induced Clostridioides difficile infection model. MCC5145 exhibited reduced nephrotoxicity at microbiologically active doses in mice compared to vancomycin. MCC5145 also showed improved activity against biofilms compared to vancomycin, both in vitro and in vivo, and a low propensity to select for drug resistance. Characterization of drug action using a transposon library bioinformatic platform showed a mechanistic distinction from other glycopeptide antibiotics.

Original language	English (US)
Article number	abj2381
Journal	Science translational medicine
Volume	14
Issue number	662
DOIs	https://doi.org/10.1126/scitranslmed.abj238
State	Published - Sep 14 2022

ASJC Scopus subject areas

General Medicine

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10.1126/scitranslmed.abj238

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Blaskovich, M. A. T., Hansford, K. A., Butler, M. S., Ramu, S., Kavanagh, A. M., Jarrad, A. M., Prasetyoputri, A., Pitt, M. E., Huang, J. X., Lindahl, F., Ziora, Z. M., Bradford, T., Muldoon, C., Rajaratnam, P., Pelingon, R., Edwards, D. J., Zhang, B., Amado, M., Elliott, A. G., ... Cooper, M. A. (2022). A lipoglycopeptide antibiotic for Gram-positive biofilm-related infections. Science translational medicine, 14(662), Article abj2381. https://doi.org/10.1126/scitranslmed.abj238

Blaskovich, MAT, Hansford, KA, Butler, MS, Ramu, S, Kavanagh, AM, Jarrad, AM, Prasetyoputri, A, Pitt, ME, Huang, JX, Lindahl, F, Ziora, ZM, Bradford, T, Muldoon, C, Rajaratnam, P, Pelingon, R, Edwards, DJ, Zhang, B, Amado, M, Elliott, AG, Zuegg, J, Coin, L, Woischnig, AK, Khanna, N, Breidenstein, E, Stincone, A, Mason, C, Khan, N, Cho, HK, Karau, MJ, Greenwood-Quaintance, KE, Patel, R, Wootton, M, James, ML, Hutton, ML, Lyras, D, Ogunniyi, AD, Mahdi, LK, Trott, DJ, Wu, X, Niles, S, Lewis, K, Smith, JR, Barber, KE, Yim, J, Rice, SA, Rybak, MJ, Ishmael, CR, Hori, KR, Bernthal, NM, Francis, KP, Roberts, JA, Paterson, DL & Cooper, MA 2022, 'A lipoglycopeptide antibiotic for Gram-positive biofilm-related infections', Science translational medicine, vol. 14, no. 662, abj2381. https://doi.org/10.1126/scitranslmed.abj238

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title = "A lipoglycopeptide antibiotic for Gram-positive biofilm-related infections",

abstract = "Drug-resistant Gram-positive bacterial infections are still a substantial burden on the public health system, with two bacteria (Staphylococcus aureus and Streptococcus pneumoniae) accounting for over 1.5 million drug-resistant infections in the United States alone in 2017. In 2019, 250,000 deaths were attributed to these pathogens globally. We have developed a preclinical glycopeptide antibiotic, MCC5145, that has excellent potency (MIC90 ≤ 0.06 μg/ml) against hundreds of isolates of methicillin-resistant S. aureus (MRSA) and other Gram-positive bacteria, with a greater than 1000-fold margin over mammalian cell cytotoxicity values. The antibiotic has therapeutic in vivo efficacy when dosed subcutaneously in multiple murine models of established bacterial infections, including thigh infection with MRSA and blood septicemia with S. pneumoniae, as well as when dosed orally in an antibiotic-induced Clostridioides difficile infection model. MCC5145 exhibited reduced nephrotoxicity at microbiologically active doses in mice compared to vancomycin. MCC5145 also showed improved activity against biofilms compared to vancomycin, both in vitro and in vivo, and a low propensity to select for drug resistance. Characterization of drug action using a transposon library bioinformatic platform showed a mechanistic distinction from other glycopeptide antibiotics.",

author = "Blaskovich, {Mark A.T.} and Hansford, {Karl A.} and Butler, {Mark S.} and Soumya Ramu and Kavanagh, {Angela M.} and Jarrad, {Angie M.} and Anggia Prasetyoputri and Pitt, {Miranda E.} and Huang, {Johnny X.} and Fredrik Lindahl and Ziora, {Zyta M.} and Tanya Bradford and Craig Muldoon and Premraj Rajaratnam and Ruby Pelingon and Edwards, {David J.} and Bing Zhang and Maite Amado and Elliott, {Alysha G.} and Johannes Zuegg and Lachlan Coin and Woischnig, {Anne Kathrin} and Nina Khanna and Elena Breidenstein and Anna Stincone and Clive Mason and Nawaz Khan and Cho, {Hye Kyung} and Karau, {Melissa J.} and Greenwood-Quaintance, {Kerryl E.} and Robin Patel and Mandy Wootton and James, {Meagan L.} and Hutton, {Melanie L.} and Dena Lyras and Ogunniyi, {Abiodun D.} and Mahdi, {Layla K.} and Trott, {Darren J.} and Xiaoqian Wu and Samantha Niles and Kim Lewis and Smith, {Jordan R.} and Barber, {Katie E.} and Juwon Yim and Rice, {Seth Alan} and Rybak, {Michael J.} and Ishmael, {Chad R.} and Hori, {Kellyn R.} and Bernthal, {Nicholas M.} and Francis, {Kevin P.} and Roberts, {Jason A.} and Paterson, {David L.} and Cooper, {Matthew A.}",

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doi = "10.1126/scitranslmed.abj238",

language = "English (US)",

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T1 - A lipoglycopeptide antibiotic for Gram-positive biofilm-related infections

AU - Blaskovich, Mark A.T.

AU - Hansford, Karl A.

AU - Butler, Mark S.

AU - Ramu, Soumya

AU - Kavanagh, Angela M.

AU - Jarrad, Angie M.

AU - Prasetyoputri, Anggia

AU - Pitt, Miranda E.

AU - Huang, Johnny X.

AU - Lindahl, Fredrik

AU - Ziora, Zyta M.

AU - Bradford, Tanya

AU - Muldoon, Craig

AU - Rajaratnam, Premraj

AU - Pelingon, Ruby

AU - Edwards, David J.

AU - Zhang, Bing

AU - Amado, Maite

AU - Elliott, Alysha G.

AU - Zuegg, Johannes

AU - Coin, Lachlan

AU - Woischnig, Anne Kathrin

AU - Khanna, Nina

AU - Breidenstein, Elena

AU - Stincone, Anna

AU - Mason, Clive

AU - Khan, Nawaz

AU - Cho, Hye Kyung

AU - Karau, Melissa J.

AU - Greenwood-Quaintance, Kerryl E.

AU - Patel, Robin

AU - Wootton, Mandy

AU - James, Meagan L.

AU - Hutton, Melanie L.

AU - Lyras, Dena

AU - Ogunniyi, Abiodun D.

AU - Mahdi, Layla K.

AU - Trott, Darren J.

AU - Wu, Xiaoqian

AU - Niles, Samantha

AU - Lewis, Kim

AU - Smith, Jordan R.

AU - Barber, Katie E.

AU - Yim, Juwon

AU - Rice, Seth Alan

AU - Rybak, Michael J.

AU - Ishmael, Chad R.

AU - Hori, Kellyn R.

AU - Bernthal, Nicholas M.

AU - Francis, Kevin P.

AU - Roberts, Jason A.

AU - Paterson, David L.

AU - Cooper, Matthew A.

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A lipoglycopeptide antibiotic for Gram-positive biofilm-related infections

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