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Profiling the in vitro and in vivo activity of streptothricin-F against carbapenem-resistant Enterobacterales: a historic scaffold with a novel mechanism of action

Kenneth P. Smith, Yoon-Suk Kang, Alex B. Green, Matthew G. Dowgiallo, Brandon C. Miller, Lucius Chiaraviglio, Katherine A. Truelson, Katelyn E. Zulauf, Shade Rodriguez, Roman Manetsch, View ORCID ProfileJames E. Kirby
doi: https://doi.org/10.1101/2021.06.14.448463
Kenneth P. Smith
aDepartment of Pathology, Beth Israel Deaconess Medical Center, Boston MA
bHarvard Medical School, Boston MA, USA
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Yoon-Suk Kang
aDepartment of Pathology, Beth Israel Deaconess Medical Center, Boston MA
bHarvard Medical School, Boston MA, USA
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Alex B. Green
aDepartment of Pathology, Beth Israel Deaconess Medical Center, Boston MA
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Matthew G. Dowgiallo
cDepartment of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Ave, Boston, MA 02115, USA
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Brandon C. Miller
cDepartment of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Ave, Boston, MA 02115, USA
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Lucius Chiaraviglio
aDepartment of Pathology, Beth Israel Deaconess Medical Center, Boston MA
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Katherine A. Truelson
aDepartment of Pathology, Beth Israel Deaconess Medical Center, Boston MA
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Katelyn E. Zulauf
aDepartment of Pathology, Beth Israel Deaconess Medical Center, Boston MA
bHarvard Medical School, Boston MA, USA
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Shade Rodriguez
aDepartment of Pathology, Beth Israel Deaconess Medical Center, Boston MA
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Roman Manetsch
cDepartment of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Ave, Boston, MA 02115, USA
dDepartment of Pharmaceutical Sciences, Northeastern University, 360 Huntington Ave, Boston, MA 02115, USA
eCenter for Drug Discovery, Northeastern University, Boston, MA 02115, USA
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James E. Kirby
aDepartment of Pathology, Beth Israel Deaconess Medical Center, Boston MA
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  • ORCID record for James E. Kirby
  • For correspondence: jekirby@bidmc.harvard.edu
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ABSTRACT

Streptothricins are components of the natural product, nourseothricin; each containing identical streptolidine and gulosamine aminosugar moieties attached to varying numbers of linked β-lysines. Nourseothricin was discovered by Waksman and colleagues in the early 1940’s, generating intense interest because of excellent Gram-negative activity. However, the natural product mixture was associated with toxicity, and subsequent exploration was limited. Here, we establish the activity spectrum of nourseothricin and its main components, streptothricin-F (S-F, one lysine) and streptothricin D (S-D, three lysines), purified to homogeneity, against highly drug-resistant, carbapenem-resistant Enterobacterales (CRE). The MIC50 and MIC90 for S-F and S-D were 2 and 4 µM, and 0.25 and 0.5 µM, respectively. S-F and nourseothricin showed rapid, bactericidal activity. S-F and S-D both showed approximately 40-fold greater selectivity for prokaryotic than eukaryotic ribosomes in in vitro translation assays. There was >10-fold in vitro selectivity of S-F compared with S-D on LLC-PK1 and J774 cell lines. In vivo, delayed renal toxicity occurred at >10-fold higher doses of S-F compared with S-D. Substantial treatment effect of S-F in the murine thigh model was observed against the otherwise pandrug-resistant, NDM-1-expressing Klebsiella pneumoniae Nevada strain at dosing levels without observable or minimal toxicity. Resistance mutations obtained in single ribosomal operon E. coli identify novel interactions with 16S rRNA helix 34, i.e., C1504A and A1196G/C conferred high level resistance to nourseothricin. Based on promising, unique activity, we suggest that the streptothricin scaffold deserves further pre-clinical exploration as a potential therapeutic for the treatment of CRE and potentially other multidrug-resistant, gram-negative pathogens.

IMPORTANCE Streptothricins are a historic class of antibiotics discovered by Waksman and colleagues in the 1940’s. Toxicities associated with the streptothricin natural product mixture, also known as nourseothricin, discouraged further development. However, we found that a component of nourseothricin, streptothricin-F, retained potent activity against contemporary carbapenem-resistant Enterobacterales with significant selectivity in in vitro and in vivo assays. This included demonstration of rapid bactericidal activity in vitro and substantial therapeutic effect in the murine thigh model against a pandrug-resistant Klebsiella pneumoniae isolate at non-toxic concentrations. Through resistance mutation analysis, we identified helix 34 of 16S rRNA in the prokaryotic ribosome, and specifically bases C1054 and A1196, as critical for streptothricin’s activity. The mechanism of action is distinct from other known translation inhibitors. Based on promising and unique activity, we believe the streptothricin scaffold deserves further pre-clinical exploration as a potential therapeutic for the treatment of CRE and potentially other multidrug-resistant, Gram-negative pathogens.

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Posted June 15, 2021.
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Profiling the in vitro and in vivo activity of streptothricin-F against carbapenem-resistant Enterobacterales: a historic scaffold with a novel mechanism of action
Kenneth P. Smith, Yoon-Suk Kang, Alex B. Green, Matthew G. Dowgiallo, Brandon C. Miller, Lucius Chiaraviglio, Katherine A. Truelson, Katelyn E. Zulauf, Shade Rodriguez, Roman Manetsch, James E. Kirby
bioRxiv 2021.06.14.448463; doi: https://doi.org/10.1101/2021.06.14.448463
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Profiling the in vitro and in vivo activity of streptothricin-F against carbapenem-resistant Enterobacterales: a historic scaffold with a novel mechanism of action
Kenneth P. Smith, Yoon-Suk Kang, Alex B. Green, Matthew G. Dowgiallo, Brandon C. Miller, Lucius Chiaraviglio, Katherine A. Truelson, Katelyn E. Zulauf, Shade Rodriguez, Roman Manetsch, James E. Kirby
bioRxiv 2021.06.14.448463; doi: https://doi.org/10.1101/2021.06.14.448463

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