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.
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: David F
authors.initials: DF
authors.lastname: Bruhn
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Samanthi L
authors.initials: SL
authors.lastname: Waidyarachchi
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Dora B
authors.initials: DB
authors.lastname: Madhura
authors.affiliation: Institut für Medizinische Mikrobiologie, Universität Zürich, Zürich, Switzerland.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Shcherbakov
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Jiuyu
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Yasser M
authors.initials: YM
authors.lastname: Abdelrahman
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA.|Biomedical Sciences Graduate Program, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Aman P
authors.initials: AP
authors.lastname: Singh
authors.affiliation: Institut für Medizinische Mikrobiologie, Universität Zürich, Zürich, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Duscha
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Chetan
authors.initials: C
authors.lastname: Rathi
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Robin B
authors.initials: RB
authors.lastname: Lee
authors.affiliation: Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Belland
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Bernd
authors.initials: B
authors.lastname: Meibohm
authors.affiliation: Infectious Diseases Department, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Jason W
authors.initials: JW
authors.lastname: Rosch
authors.affiliation: Institut für Medizinische Mikrobiologie, Universität Zürich, Zürich, Switzerland.
authors.forename: Erik C
authors.initials: EC
authors.lastname: Böttger
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Lee
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects* / Q000378:metabolism / Q000472:pathogenicity; D001426:Bacterial Proteins / Q000096:biosynthesis; D002522:Chlorocebus aethiops; D003198:Computer Simulation; D017076:Computer-Aided Design; D004195:Disease Models, Animal; D055808:Drug Discovery; D004347:Drug Interactions; D024881:Drug Resistance, Bacterial; D004355:Drug Stability; D006801:Humans; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D012141:Respiratory Tract Infections / Q000175:diagnosis / Q000188:drug therapy* / Q000382:microbiology; D012270:Ribosomes / Q000187:drug effects / Q000378:metabolism; D015231:Sexually Transmitted Diseases, Bacterial / Q000175:diagnosis / Q000188:drug therapy* / Q000382:microbiology; D000198:Spectinomycin / Q000009:adverse effects / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014709:Vero Cells
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D000198:Spectinomycin