Unstable Mechanisms of Resistance to Inhibitors of <named-content content-type="genus-species">Escherichia coli</named-content> Lipoprotein Signal Peptidase

ABSTRACT Clinical development of antibiotics with novel mechanisms of action to kill pathogenic bacteria is challenging, in part, due to the inevitable emergence of resistance. A phenomenon of potential clinical importance that is broadly overlooked in preclinical development is heteroresistance, an...

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Autores principales:	Homer Pantua, Elizabeth Skippington, Marie-Gabrielle Braun, Cameron L. Noland, Jingyu Diao, Yutian Peng, Susan L. Gloor, Donghong Yan, Jing Kang, Anand Kumar Katakam, Janina Reeder, Georgette M. Castanedo, Keira Garland, Laszlo Komuves, Meredith Sagolla, Cary D. Austin, Jeremy Murray, Yiming Xu, Zora Modrusan, Min Xu, Emily J. Hanan, Sharookh B. Kapadia
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	heteroresistance lipoprotein Lpp LspA globomycin Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/ad7dc0127d394ca78d233d455e860331
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spelling	oai:doaj.org-article:ad7dc0127d394ca78d233d455e8603312021-11-15T16:19:07ZUnstable Mechanisms of Resistance to Inhibitors of <named-content content-type="genus-species">Escherichia coli</named-content> Lipoprotein Signal Peptidase10.1128/mBio.02018-202150-7511https://doaj.org/article/ad7dc0127d394ca78d233d455e8603312020-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02018-20https://doaj.org/toc/2150-7511ABSTRACT Clinical development of antibiotics with novel mechanisms of action to kill pathogenic bacteria is challenging, in part, due to the inevitable emergence of resistance. A phenomenon of potential clinical importance that is broadly overlooked in preclinical development is heteroresistance, an often-unstable phenotype in which subpopulations of bacterial cells show decreased antibiotic susceptibility relative to the dominant population. Here, we describe a new globomycin analog, G0790, with potent activity against the Escherichia coli type II signal peptidase LspA and uncover two novel resistance mechanisms to G0790 in the clinical uropathogenic E. coli strain CFT073. Building on the previous finding that complete deletion of Lpp, the major Gram-negative outer membrane lipoprotein, leads to globomycin resistance, we also find that an unexpectedly modest decrease in Lpp levels mediated by insertion-based disruption of regulatory elements is sufficient to confer G0790 resistance and increase sensitivity to serum killing. In addition, we describe a heteroresistance phenotype mediated by genomic amplifications of lspA that result in increased LspA levels sufficient to overcome inhibition by G0790 in culture. These genomic amplifications are highly unstable and are lost after as few as two subcultures in the absence of G0790, which places amplification-containing resistant strains at high risk of being misclassified as susceptible by routine antimicrobial susceptibility testing. In summary, our study uncovers two vastly different mechanisms of resistance to LspA inhibitors in E. coli and emphasizes the importance of considering the potential impact of unstable and heterogenous phenotypes when developing antibiotics for clinical use. IMPORTANCE Despite increasing evidence suggesting that antibiotic heteroresistance can lead to treatment failure, the significance of this phenomena in the clinic is not well understood, because many clinical antibiotic susceptibility testing approaches lack the resolution needed to reliably classify heteroresistant strains. Here we present G0790, a new globomycin analog and potent inhibitor of the Escherichia coli type II signal peptidase LspA. We demonstrate that in addition to previously known mechanisms of resistance to LspA inhibitors, unstable genomic amplifications containing lspA can lead to modest yet biologically significant increases in LspA protein levels that confer a heteroresistance phenotype.Homer PantuaElizabeth SkippingtonMarie-Gabrielle BraunCameron L. NolandJingyu DiaoYutian PengSusan L. GloorDonghong YanJing KangAnand Kumar KatakamJanina ReederGeorgette M. CastanedoKeira GarlandLaszlo KomuvesMeredith SagollaCary D. AustinJeremy MurrayYiming XuZora ModrusanMin XuEmily J. HananSharookh B. KapadiaAmerican Society for MicrobiologyarticleheteroresistancelipoproteinLppLspAglobomycinMicrobiologyQR1-502ENmBio, Vol 11, Iss 5 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	heteroresistance lipoprotein Lpp LspA globomycin Microbiology QR1-502
spellingShingle	heteroresistance lipoprotein Lpp LspA globomycin Microbiology QR1-502 Homer Pantua Elizabeth Skippington Marie-Gabrielle Braun Cameron L. Noland Jingyu Diao Yutian Peng Susan L. Gloor Donghong Yan Jing Kang Anand Kumar Katakam Janina Reeder Georgette M. Castanedo Keira Garland Laszlo Komuves Meredith Sagolla Cary D. Austin Jeremy Murray Yiming Xu Zora Modrusan Min Xu Emily J. Hanan Sharookh B. Kapadia Unstable Mechanisms of Resistance to Inhibitors of <named-content content-type="genus-species">Escherichia coli</named-content> Lipoprotein Signal Peptidase
description	ABSTRACT Clinical development of antibiotics with novel mechanisms of action to kill pathogenic bacteria is challenging, in part, due to the inevitable emergence of resistance. A phenomenon of potential clinical importance that is broadly overlooked in preclinical development is heteroresistance, an often-unstable phenotype in which subpopulations of bacterial cells show decreased antibiotic susceptibility relative to the dominant population. Here, we describe a new globomycin analog, G0790, with potent activity against the Escherichia coli type II signal peptidase LspA and uncover two novel resistance mechanisms to G0790 in the clinical uropathogenic E. coli strain CFT073. Building on the previous finding that complete deletion of Lpp, the major Gram-negative outer membrane lipoprotein, leads to globomycin resistance, we also find that an unexpectedly modest decrease in Lpp levels mediated by insertion-based disruption of regulatory elements is sufficient to confer G0790 resistance and increase sensitivity to serum killing. In addition, we describe a heteroresistance phenotype mediated by genomic amplifications of lspA that result in increased LspA levels sufficient to overcome inhibition by G0790 in culture. These genomic amplifications are highly unstable and are lost after as few as two subcultures in the absence of G0790, which places amplification-containing resistant strains at high risk of being misclassified as susceptible by routine antimicrobial susceptibility testing. In summary, our study uncovers two vastly different mechanisms of resistance to LspA inhibitors in E. coli and emphasizes the importance of considering the potential impact of unstable and heterogenous phenotypes when developing antibiotics for clinical use. IMPORTANCE Despite increasing evidence suggesting that antibiotic heteroresistance can lead to treatment failure, the significance of this phenomena in the clinic is not well understood, because many clinical antibiotic susceptibility testing approaches lack the resolution needed to reliably classify heteroresistant strains. Here we present G0790, a new globomycin analog and potent inhibitor of the Escherichia coli type II signal peptidase LspA. We demonstrate that in addition to previously known mechanisms of resistance to LspA inhibitors, unstable genomic amplifications containing lspA can lead to modest yet biologically significant increases in LspA protein levels that confer a heteroresistance phenotype.
format	article
author	Homer Pantua Elizabeth Skippington Marie-Gabrielle Braun Cameron L. Noland Jingyu Diao Yutian Peng Susan L. Gloor Donghong Yan Jing Kang Anand Kumar Katakam Janina Reeder Georgette M. Castanedo Keira Garland Laszlo Komuves Meredith Sagolla Cary D. Austin Jeremy Murray Yiming Xu Zora Modrusan Min Xu Emily J. Hanan Sharookh B. Kapadia
author_facet	Homer Pantua Elizabeth Skippington Marie-Gabrielle Braun Cameron L. Noland Jingyu Diao Yutian Peng Susan L. Gloor Donghong Yan Jing Kang Anand Kumar Katakam Janina Reeder Georgette M. Castanedo Keira Garland Laszlo Komuves Meredith Sagolla Cary D. Austin Jeremy Murray Yiming Xu Zora Modrusan Min Xu Emily J. Hanan Sharookh B. Kapadia
author_sort	Homer Pantua
title	Unstable Mechanisms of Resistance to Inhibitors of <named-content content-type="genus-species">Escherichia coli</named-content> Lipoprotein Signal Peptidase
title_short	Unstable Mechanisms of Resistance to Inhibitors of <named-content content-type="genus-species">Escherichia coli</named-content> Lipoprotein Signal Peptidase
title_full	Unstable Mechanisms of Resistance to Inhibitors of <named-content content-type="genus-species">Escherichia coli</named-content> Lipoprotein Signal Peptidase
title_fullStr	Unstable Mechanisms of Resistance to Inhibitors of <named-content content-type="genus-species">Escherichia coli</named-content> Lipoprotein Signal Peptidase
title_full_unstemmed	Unstable Mechanisms of Resistance to Inhibitors of <named-content content-type="genus-species">Escherichia coli</named-content> Lipoprotein Signal Peptidase
title_sort	unstable mechanisms of resistance to inhibitors of <named-content content-type="genus-species">escherichia coli</named-content> lipoprotein signal peptidase
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/ad7dc0127d394ca78d233d455e860331
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Unstable Mechanisms of Resistance to Inhibitors of <named-content content-type="genus-species">Escherichia coli</named-content> Lipoprotein Signal Peptidase

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