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Experimental Therapeutics

A Novel Inhibitor of the LolCDE ABC Transporter Essential for Lipoprotein Trafficking in Gram-Negative Bacteria

Nicholas N. Nickerson, Christine C. Jao, Yiming Xu, John Quinn, Elizabeth Skippington, Mary Kate Alexander, Anh Miu, Nicholas Skelton, Jessica V. Hankins, Michael S. Lopez, Christopher M. Koth, Steven Rutherford, Mireille Nishiyama
Nicholas N. Nickerson
aDepartment of Infectious Diseases, Genentech, Inc., South San Francisco, California, USA
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Christine C. Jao
bDepartment of Structural Biology, Genentech, Inc., South San Francisco, California, USA
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Yiming Xu
dDepartment of Biochemical and Cellular Pharmacology, Genentech, Inc., South San Francisco, California, USA
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John Quinn
dDepartment of Biochemical and Cellular Pharmacology, Genentech, Inc., South San Francisco, California, USA
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Elizabeth Skippington
cDepartment of Bioinformatics and Computational Biology, Genentech, Inc., South San Francisco, California, USA
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Mary Kate Alexander
aDepartment of Infectious Diseases, Genentech, Inc., South San Francisco, California, USA
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Anh Miu
dDepartment of Biochemical and Cellular Pharmacology, Genentech, Inc., South San Francisco, California, USA
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Nicholas Skelton
eDepartment of Discovery Chemistry, Genentech, Inc., South San Francisco, California, USA
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Jessica V. Hankins
aDepartment of Infectious Diseases, Genentech, Inc., South San Francisco, California, USA
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Michael S. Lopez
aDepartment of Infectious Diseases, Genentech, Inc., South San Francisco, California, USA
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Christopher M. Koth
bDepartment of Structural Biology, Genentech, Inc., South San Francisco, California, USA
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Steven Rutherford
aDepartment of Infectious Diseases, Genentech, Inc., South San Francisco, California, USA
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Mireille Nishiyama
aDepartment of Infectious Diseases, Genentech, Inc., South San Francisco, California, USA
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DOI: 10.1128/AAC.02151-17
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ABSTRACT

The outer membrane is an essential structural component of Gram-negative bacteria that is composed of lipoproteins, lipopolysaccharides, phospholipids, and integral β-barrel membrane proteins. A dedicated machinery, called the Lol system, ensures proper trafficking of lipoproteins from the inner to the outer membrane. The LolCDE ABC transporter is the inner membrane component, which is essential for bacterial viability. Here, we report a novel pyrrolopyrimidinedione compound, G0507, which was identified in a phenotypic screen for inhibitors of Escherichia coli growth followed by selection of compounds that induced the extracytoplasmic σE stress response. Mutations in lolC, lolD, and lolE conferred resistance to G0507, suggesting LolCDE as its molecular target. Treatment of E. coli cells with G0507 resulted in accumulation of fully processed Lpp, an outer membrane lipoprotein, in the inner membrane. Using purified protein complexes, we found that G0507 binds to LolCDE and stimulates its ATPase activity. G0507 still binds to LolCDE harboring a Q258K substitution in LolC (LolCQ258K), which confers high-level resistance to G0507 in vivo but no longer stimulates ATPase activity. Our work demonstrates that G0507 has significant promise as a chemical probe to dissect lipoprotein trafficking in Gram-negative bacteria.

FOOTNOTES

    • Received 18 October 2017.
    • Returned for modification 10 November 2017.
    • Accepted 6 January 2018.
    • Accepted manuscript posted online 16 January 2018.
  • Supplemental material for this article may be found at https://doi.org/10.1128/AAC.02151-17.

  • Copyright © 2018 American Society for Microbiology.

All Rights Reserved.

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A Novel Inhibitor of the LolCDE ABC Transporter Essential for Lipoprotein Trafficking in Gram-Negative Bacteria
Nicholas N. Nickerson, Christine C. Jao, Yiming Xu, John Quinn, Elizabeth Skippington, Mary Kate Alexander, Anh Miu, Nicholas Skelton, Jessica V. Hankins, Michael S. Lopez, Christopher M. Koth, Steven Rutherford, Mireille Nishiyama
Antimicrobial Agents and Chemotherapy Mar 2018, 62 (4) e02151-17; DOI: 10.1128/AAC.02151-17

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A Novel Inhibitor of the LolCDE ABC Transporter Essential for Lipoprotein Trafficking in Gram-Negative Bacteria
Nicholas N. Nickerson, Christine C. Jao, Yiming Xu, John Quinn, Elizabeth Skippington, Mary Kate Alexander, Anh Miu, Nicholas Skelton, Jessica V. Hankins, Michael S. Lopez, Christopher M. Koth, Steven Rutherford, Mireille Nishiyama
Antimicrobial Agents and Chemotherapy Mar 2018, 62 (4) e02151-17; DOI: 10.1128/AAC.02151-17
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KEYWORDS

LolCDE
antibiotic discovery
lipoprotein trafficking
outer membrane biogenesis
phenotypic assay
stress response

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