Aminomethyl spectinomycins as therapeutics for drug-resistant respiratory tract and sexually transmitted bacterial infections

David F. Bruhn, Samanthi L. Waidyarachchi, Dora B. Madhura, Dimitri Shcherbakov, Zhong Zheng, Jiuyu Liu, Yasser M. Abdelrahman, Aman P. Singh, Stefan Duscha, Chetan Rathi, Robin B. Lee, Robert J. Belland, Bernd Meibohm, Jason W. Rosch, Erik C. Böttger, Richard E. Lee

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

The antibiotic spectinomycin is a potent inhibitor of bacterial protein synthesis with a unique mechanism of action and an excellent safety index, but it lacks antibacterial activity against most clinically important pathogens. A series of N-benzyl-substituted 3'-(R)-3'-aminomethyl-3'-hydroxy spectinomycins was developed on the basis of a computational analysis of the aminomethyl spectinomycin binding site and structure-guided synthesis. These compounds had ribosomal inhibition values comparable to spectinomycin but showed increased potency against the common respiratory tract pathogens Streptococcus pneumoniae, Haemophilus influenzae, Legionella pneumophila, and Moraxella catarrhalis, as well as the sexually transmitted bacteria Neisseria gonorrhoeae and Chlamydia trachomatis. Non-ribosome-binding 3'-(S) isomers of the lead compounds demonstrated weak inhibitory activity in in vitro protein translation assays and poor antibacterial activity, indicating that the antibacterial activity of the series remains on target against the ribosome. Compounds also demonstrated no mammalian cytotoxicity, improved microsomal stability, and favorable pharmacokinetic properties in rats. The lead compound from the series exhibited excellent chemical stability superior to spectinomycin; no interaction with a panel of human receptors and drug metabolism enzymes, suggesting low potential for adverse reactions or drug-drug interactions in vivo; activity in vitro against a panel of penicillin-, macrolide-, and cephalosporin-resistant S. pneumoniae clinical isolates; and the ability to cure mice of fatal pneumococcal pneumonia and sepsis at a dose of 5 mg/kg. Together, these studies indicate that N-benzyl aminomethyl spectinomycins are suitable for further development to treat drug-resistant respiratory tract and sexually transmitted bacterial infections.

Original languageEnglish (US)
JournalScience Translational Medicine
Volume7
Issue number288
DOIs
StatePublished - May 20 2015

Fingerprint

Spectinomycin
Sexually Transmitted Diseases
Bacterial Infections
Respiratory System
Pharmaceutical Preparations
Streptococcus pneumoniae
Therapeutics
Pneumococcal Pneumonia
Drug Receptors
Moraxella (Branhamella) catarrhalis
Legionella pneumophila
Protein Synthesis Inhibitors
Bacterial Proteins
Neisseria gonorrhoeae
Chlamydia trachomatis
Macrolides
Haemophilus influenzae
Protein Biosynthesis
Cephalosporins
Drug-Related Side Effects and Adverse Reactions

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Aminomethyl spectinomycins as therapeutics for drug-resistant respiratory tract and sexually transmitted bacterial infections. / Bruhn, David F.; Waidyarachchi, Samanthi L.; Madhura, Dora B.; Shcherbakov, Dimitri; Zheng, Zhong; Liu, Jiuyu; Abdelrahman, Yasser M.; Singh, Aman P.; Duscha, Stefan; Rathi, Chetan; Lee, Robin B.; Belland, Robert J.; Meibohm, Bernd; Rosch, Jason W.; Böttger, Erik C.; Lee, Richard E.

In: Science Translational Medicine, Vol. 7, No. 288, 20.05.2015.

Research output: Contribution to journalArticle

Bruhn, DF, Waidyarachchi, SL, Madhura, DB, Shcherbakov, D, Zheng, Z, Liu, J, Abdelrahman, YM, Singh, AP, Duscha, S, Rathi, C, Lee, RB, Belland, RJ, Meibohm, B, Rosch, JW, Böttger, EC & Lee, RE 2015, 'Aminomethyl spectinomycins as therapeutics for drug-resistant respiratory tract and sexually transmitted bacterial infections', Science Translational Medicine, vol. 7, no. 288. https://doi.org/10.1126/scitranslmed.3010572
Bruhn, David F. ; Waidyarachchi, Samanthi L. ; Madhura, Dora B. ; Shcherbakov, Dimitri ; Zheng, Zhong ; Liu, Jiuyu ; Abdelrahman, Yasser M. ; Singh, Aman P. ; Duscha, Stefan ; Rathi, Chetan ; Lee, Robin B. ; Belland, Robert J. ; Meibohm, Bernd ; Rosch, Jason W. ; Böttger, Erik C. ; Lee, Richard E. / Aminomethyl spectinomycins as therapeutics for drug-resistant respiratory tract and sexually transmitted bacterial infections. In: Science Translational Medicine. 2015 ; Vol. 7, No. 288.
@article{f6a3d1c2439e4d63943114209b3ffd85,
title = "Aminomethyl spectinomycins as therapeutics for drug-resistant respiratory tract and sexually transmitted bacterial infections",
abstract = "The antibiotic spectinomycin is a potent inhibitor of bacterial protein synthesis with a unique mechanism of action and an excellent safety index, but it lacks antibacterial activity against most clinically important pathogens. A series of N-benzyl-substituted 3'-(R)-3'-aminomethyl-3'-hydroxy spectinomycins was developed on the basis of a computational analysis of the aminomethyl spectinomycin binding site and structure-guided synthesis. These compounds had ribosomal inhibition values comparable to spectinomycin but showed increased potency against the common respiratory tract pathogens Streptococcus pneumoniae, Haemophilus influenzae, Legionella pneumophila, and Moraxella catarrhalis, as well as the sexually transmitted bacteria Neisseria gonorrhoeae and Chlamydia trachomatis. Non-ribosome-binding 3'-(S) isomers of the lead compounds demonstrated weak inhibitory activity in in vitro protein translation assays and poor antibacterial activity, indicating that the antibacterial activity of the series remains on target against the ribosome. Compounds also demonstrated no mammalian cytotoxicity, improved microsomal stability, and favorable pharmacokinetic properties in rats. The lead compound from the series exhibited excellent chemical stability superior to spectinomycin; no interaction with a panel of human receptors and drug metabolism enzymes, suggesting low potential for adverse reactions or drug-drug interactions in vivo; activity in vitro against a panel of penicillin-, macrolide-, and cephalosporin-resistant S. pneumoniae clinical isolates; and the ability to cure mice of fatal pneumococcal pneumonia and sepsis at a dose of 5 mg/kg. Together, these studies indicate that N-benzyl aminomethyl spectinomycins are suitable for further development to treat drug-resistant respiratory tract and sexually transmitted bacterial infections.",
author = "Bruhn, {David F.} and Waidyarachchi, {Samanthi L.} and Madhura, {Dora B.} and Dimitri Shcherbakov and Zhong Zheng and Jiuyu Liu and Abdelrahman, {Yasser M.} and Singh, {Aman P.} and Stefan Duscha and Chetan Rathi and Lee, {Robin B.} and Belland, {Robert J.} and Bernd Meibohm and Rosch, {Jason W.} and B{\"o}ttger, {Erik C.} and Lee, {Richard E.}",
year = "2015",
month = "5",
day = "20",
doi = "10.1126/scitranslmed.3010572",
language = "English (US)",
volume = "7",
journal = "Science Translational Medicine",
issn = "1946-6234",
publisher = "American Association for the Advancement of Science",
number = "288",

}

TY - JOUR

T1 - Aminomethyl spectinomycins as therapeutics for drug-resistant respiratory tract and sexually transmitted bacterial infections

AU - Bruhn, David F.

AU - Waidyarachchi, Samanthi L.

AU - Madhura, Dora B.

AU - Shcherbakov, Dimitri

AU - Zheng, Zhong

AU - Liu, Jiuyu

AU - Abdelrahman, Yasser M.

AU - Singh, Aman P.

AU - Duscha, Stefan

AU - Rathi, Chetan

AU - Lee, Robin B.

AU - Belland, Robert J.

AU - Meibohm, Bernd

AU - Rosch, Jason W.

AU - Böttger, Erik C.

AU - Lee, Richard E.

PY - 2015/5/20

Y1 - 2015/5/20

N2 - The antibiotic spectinomycin is a potent inhibitor of bacterial protein synthesis with a unique mechanism of action and an excellent safety index, but it lacks antibacterial activity against most clinically important pathogens. A series of N-benzyl-substituted 3'-(R)-3'-aminomethyl-3'-hydroxy spectinomycins was developed on the basis of a computational analysis of the aminomethyl spectinomycin binding site and structure-guided synthesis. These compounds had ribosomal inhibition values comparable to spectinomycin but showed increased potency against the common respiratory tract pathogens Streptococcus pneumoniae, Haemophilus influenzae, Legionella pneumophila, and Moraxella catarrhalis, as well as the sexually transmitted bacteria Neisseria gonorrhoeae and Chlamydia trachomatis. Non-ribosome-binding 3'-(S) isomers of the lead compounds demonstrated weak inhibitory activity in in vitro protein translation assays and poor antibacterial activity, indicating that the antibacterial activity of the series remains on target against the ribosome. Compounds also demonstrated no mammalian cytotoxicity, improved microsomal stability, and favorable pharmacokinetic properties in rats. The lead compound from the series exhibited excellent chemical stability superior to spectinomycin; no interaction with a panel of human receptors and drug metabolism enzymes, suggesting low potential for adverse reactions or drug-drug interactions in vivo; activity in vitro against a panel of penicillin-, macrolide-, and cephalosporin-resistant S. pneumoniae clinical isolates; and the ability to cure mice of fatal pneumococcal pneumonia and sepsis at a dose of 5 mg/kg. Together, these studies indicate that N-benzyl aminomethyl spectinomycins are suitable for further development to treat drug-resistant respiratory tract and sexually transmitted bacterial infections.

AB - The antibiotic spectinomycin is a potent inhibitor of bacterial protein synthesis with a unique mechanism of action and an excellent safety index, but it lacks antibacterial activity against most clinically important pathogens. A series of N-benzyl-substituted 3'-(R)-3'-aminomethyl-3'-hydroxy spectinomycins was developed on the basis of a computational analysis of the aminomethyl spectinomycin binding site and structure-guided synthesis. These compounds had ribosomal inhibition values comparable to spectinomycin but showed increased potency against the common respiratory tract pathogens Streptococcus pneumoniae, Haemophilus influenzae, Legionella pneumophila, and Moraxella catarrhalis, as well as the sexually transmitted bacteria Neisseria gonorrhoeae and Chlamydia trachomatis. Non-ribosome-binding 3'-(S) isomers of the lead compounds demonstrated weak inhibitory activity in in vitro protein translation assays and poor antibacterial activity, indicating that the antibacterial activity of the series remains on target against the ribosome. Compounds also demonstrated no mammalian cytotoxicity, improved microsomal stability, and favorable pharmacokinetic properties in rats. The lead compound from the series exhibited excellent chemical stability superior to spectinomycin; no interaction with a panel of human receptors and drug metabolism enzymes, suggesting low potential for adverse reactions or drug-drug interactions in vivo; activity in vitro against a panel of penicillin-, macrolide-, and cephalosporin-resistant S. pneumoniae clinical isolates; and the ability to cure mice of fatal pneumococcal pneumonia and sepsis at a dose of 5 mg/kg. Together, these studies indicate that N-benzyl aminomethyl spectinomycins are suitable for further development to treat drug-resistant respiratory tract and sexually transmitted bacterial infections.

UR - http://www.scopus.com/inward/record.url?scp=84929833719&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84929833719&partnerID=8YFLogxK

U2 - 10.1126/scitranslmed.3010572

DO - 10.1126/scitranslmed.3010572

M3 - Article

VL - 7

JO - Science Translational Medicine

JF - Science Translational Medicine

SN - 1946-6234

IS - 288

ER -