A new antibiotic with potent activity targets MscL

Irene Iscla; Robin Wray; Paul Blount; Jonah Larkins-Ford; Annie Conery; Frederick Ausubel; Soumya Ramu; Angela Kavanagh; Johnny Huang; Mark Blaskovich; Matthew Cooper; Andres Obregon-Henao; Ian Orme; Edwin Tjandra; Uwe Stroeher; Melissa Brown; Peta Macardle; Nicholas VanHolstPellekaan; Chee Ling Tong; Ashley Slattery; Christopher Gibson; Colin Raston; Ramiz Boulos

doi:10.1038/ja.2015.4

A new antibiotic with potent activity targets MscL

Irene Iscla, Robin Wray, Paul Blount, Jonah Larkins-Ford, Annie Conery, Frederick Ausubel, Soumya Ramu, Angela Kavanagh, Johnny Huang, Mark Blaskovich, Matthew Cooper, Andres Obregon-Henao, Ian Orme, Edwin Tjandra, Uwe Stroeher, Melissa Brown, Peta Macardle, Nicholas VanHolstPellekaan, Chee Ling Tong, Ashley SlatteryChristopher Gibson, Colin Raston, Ramiz Boulos

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Abstract

The growing problem of antibiotic-resistant bacteria is a major threat to human health. Paradoxically, new antibiotic discovery is declining, with most of the recently approved antibiotics corresponding to new uses for old antibiotics or structurally similar derivatives of known antibiotics. We used an in silico approach to design a new class of nontoxic antimicrobials for the bacteria-specific mechanosensitive ion channel of large conductance, MscL. One antimicrobial of this class, compound 10, is effective against methicillin-resistant Staphylococcus aureus with no cytotoxicity in human cell lines at the therapeutic concentrations. As predicted from in silico modeling, we show that the mechanism of action of compound 10 is at least partly dependent on interactions with MscL. Moreover we show that compound 10 cured a methicillin-resistant S. aureus infection in the model nematode Caenorhabditis elegans. Our work shows that compound 10, and other drugs that target MscL, are potentially important therapeutics against antibiotic-resistant bacterial infections.

Original language	English
Pages (from-to)	453-462
Number of pages	10
Journal	JOURNAL OF ANTIBIOTICS
Volume	68
Issue number	7
Early online date	2015
DOIs	https://doi.org/10.1038/ja.2015.4
Publication status	Published - 29 Jul 2015

Bibliographical note

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

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Iscla_New_P2015Final published version, 1.15 MBLicence: CC BY-NC-ND

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Iscla, I., Wray, R., Blount, P., Larkins-Ford, J., Conery, A., Ausubel, F., Ramu, S., Kavanagh, A., Huang, J., Blaskovich, M., Cooper, M., Obregon-Henao, A., Orme, I., Tjandra, E., Stroeher, U., Brown, M., Macardle, P., VanHolstPellekaan, N., Tong, C. L., ... Boulos, R. (2015). A new antibiotic with potent activity targets MscL. JOURNAL OF ANTIBIOTICS, 68(7), 453-462. https://doi.org/10.1038/ja.2015.4

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title = "A new antibiotic with potent activity targets MscL",

abstract = "The growing problem of antibiotic-resistant bacteria is a major threat to human health. Paradoxically, new antibiotic discovery is declining, with most of the recently approved antibiotics corresponding to new uses for old antibiotics or structurally similar derivatives of known antibiotics. We used an in silico approach to design a new class of nontoxic antimicrobials for the bacteria-specific mechanosensitive ion channel of large conductance, MscL. One antimicrobial of this class, compound 10, is effective against methicillin-resistant Staphylococcus aureus with no cytotoxicity in human cell lines at the therapeutic concentrations. As predicted from in silico modeling, we show that the mechanism of action of compound 10 is at least partly dependent on interactions with MscL. Moreover we show that compound 10 cured a methicillin-resistant S. aureus infection in the model nematode Caenorhabditis elegans. Our work shows that compound 10, and other drugs that target MscL, are potentially important therapeutics against antibiotic-resistant bacterial infections.",

author = "Irene Iscla and Robin Wray and Paul Blount and Jonah Larkins-Ford and Annie Conery and Frederick Ausubel and Soumya Ramu and Angela Kavanagh and Johnny Huang and Mark Blaskovich and Matthew Cooper and Andres Obregon-Henao and Ian Orme and Edwin Tjandra and Uwe Stroeher and Melissa Brown and Peta Macardle and Nicholas VanHolstPellekaan and Tong, {Chee Ling} and Ashley Slattery and Christopher Gibson and Colin Raston and Ramiz Boulos",

note = "This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. The images or other third party material in this article are included in the article{\textquoteright}s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/",

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Iscla, I, Wray, R, Blount, P, Larkins-Ford, J, Conery, A, Ausubel, F, Ramu, S, Kavanagh, A, Huang, J, Blaskovich, M, Cooper, M, Obregon-Henao, A, Orme, I, Tjandra, E, Stroeher, U, Brown, M, Macardle, P, VanHolstPellekaan, N, Tong, CL, Slattery, A, Gibson, C , Raston, C & Boulos, R 2015, 'A new antibiotic with potent activity targets MscL', JOURNAL OF ANTIBIOTICS, vol. 68, no. 7, pp. 453-462. https://doi.org/10.1038/ja.2015.4

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AU - Iscla, Irene

AU - Wray, Robin

AU - Blount, Paul

AU - Larkins-Ford, Jonah

AU - Conery, Annie

AU - Ausubel, Frederick

AU - Ramu, Soumya

AU - Kavanagh, Angela

AU - Huang, Johnny

AU - Blaskovich, Mark

AU - Cooper, Matthew

AU - Obregon-Henao, Andres

AU - Orme, Ian

AU - Tjandra, Edwin

AU - Stroeher, Uwe

AU - Brown, Melissa

AU - Macardle, Peta

AU - VanHolstPellekaan, Nicholas

AU - Tong, Chee Ling

AU - Slattery, Ashley

AU - Gibson, Christopher

AU - Raston, Colin

AU - Boulos, Ramiz

N1 - This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

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Y1 - 2015/7/29

N2 - The growing problem of antibiotic-resistant bacteria is a major threat to human health. Paradoxically, new antibiotic discovery is declining, with most of the recently approved antibiotics corresponding to new uses for old antibiotics or structurally similar derivatives of known antibiotics. We used an in silico approach to design a new class of nontoxic antimicrobials for the bacteria-specific mechanosensitive ion channel of large conductance, MscL. One antimicrobial of this class, compound 10, is effective against methicillin-resistant Staphylococcus aureus with no cytotoxicity in human cell lines at the therapeutic concentrations. As predicted from in silico modeling, we show that the mechanism of action of compound 10 is at least partly dependent on interactions with MscL. Moreover we show that compound 10 cured a methicillin-resistant S. aureus infection in the model nematode Caenorhabditis elegans. Our work shows that compound 10, and other drugs that target MscL, are potentially important therapeutics against antibiotic-resistant bacterial infections.

AB - The growing problem of antibiotic-resistant bacteria is a major threat to human health. Paradoxically, new antibiotic discovery is declining, with most of the recently approved antibiotics corresponding to new uses for old antibiotics or structurally similar derivatives of known antibiotics. We used an in silico approach to design a new class of nontoxic antimicrobials for the bacteria-specific mechanosensitive ion channel of large conductance, MscL. One antimicrobial of this class, compound 10, is effective against methicillin-resistant Staphylococcus aureus with no cytotoxicity in human cell lines at the therapeutic concentrations. As predicted from in silico modeling, we show that the mechanism of action of compound 10 is at least partly dependent on interactions with MscL. Moreover we show that compound 10 cured a methicillin-resistant S. aureus infection in the model nematode Caenorhabditis elegans. Our work shows that compound 10, and other drugs that target MscL, are potentially important therapeutics against antibiotic-resistant bacterial infections.

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U2 - 10.1038/ja.2015.4

DO - 10.1038/ja.2015.4

M3 - Article

SN - 0021-8820

VL - 68

SP - 453

EP - 462

JO - JOURNAL OF ANTIBIOTICS

JF - JOURNAL OF ANTIBIOTICS

IS - 7

ER -

A new antibiotic with potent activity targets MscL

Abstract

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UN SDGs

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