Princeton University

Harvard College

Transcell Technologies, Inc.

The Ohio State University

Daniel E Kahne

Suzanne Walker Kahne

Min Ge

Hirokazu Tsukamoto

Christopher Thompson

Seketsu Fukuzawa

Dorothee Andres

Thomas J Silhavy

Marcin Grabowicz

Matthew Lebar

Robert Kerns

Kevin Tyler Chapman

Ronald M Kim

Suzanne Walker

Lin Yan

Vadim Baidin

Michael D Mandler

Emma Doud

Christian M Gampe

Yi Zhang

Michael J Sofia

Nicole T Hatzenbuhler

Carol M Taylor

Robert A Goodnow, Jr

Jeff Gildersleeve

Bohdan Ostash

Xiaonan Lin

Shinichiro Fuse

Masaatsu Adachi

Natividad Ruiz

Disclosed are aminocoumarin compounds, pharmaceutical compositions containing aminocoumarin compounds, and methods of their use, e.g., in the treatment of a Gram-negative bacterial infection.

Aminocoumarin compounds and methods of their use

Disclosed herein are secondary amine compounds that inhibit tRNA synthetase. The compounds of the invention are useful in inhibiting tRNA synthetase in Gram-negative bacteria and are useful in killing Gram-negative bacteria. The secondary amine compounds of the invention are also useful in the treatment of tuberculosis.

TRNA synthetase inhibitors

This invention features new compositions and methods that are useful in treating a host with a Gram-negative bacterial infection. Combination therapies comprising an aminocoumarin compound and a polymyxin compound are disclosed, including certain combinations that exhibit synergistic effects. Furthermore, aminocoumarin compounds are described having altered inhibition of DNA gyrase in Gram-negative bacteria and/or the ability to target the transport proteins responsible for assembling lipopolysaccharide in the outer membrane of Gram-negative bacteria.

Methods of treatment for bacterial infections

The present disclosure generally relates to genetic engineering of bacteria. More particularly, the present disclosure describes genetic engineering ofto create mutant O-antigen ligase, as well as novel lipopolysaccharide molecules resulting from that genetic engineering. Methods for using those novel molecules are also described.

Modified lipopolysaccharide glycoform and method of use

The present invention provides moenomycin-based probe compounds of Formula (I) for use in screening inhibitors of bacterial glycosyltransferases. The present invention also provides bacterial glycosyltransferase screening assays using compounds of Formula (I).

Methods and compounds for identifying glycosyltransferase inhibitors

The present invention provides methods of synthesizing moenomycin analogs of Formula (I). The present invention also provides compositions comprising a compound of Formula (I) and kits for synthesizing compounds of Formula (I). 

Chemoenzymatic methods for synthesizing moenomycin analogs

The present invention provides compounds of Formula (I); or a pharmaceutically acceptable form thereof; wherein R,R,R,R,R,R,R, and Rare as defined herein, and G is a group of Formula (a), (b), or (c): Formula (II), wherein X; X, X, X, X, X, X, Y, R, R, R, a, d, e, x, n, and m are as defined herein. The present invention further provides pharmaceutical compositions comprising a compound of Formula (I), kits comprising such compositions, methods of use and treatment, and preparative methods. 

Moenomycin analogs, methods of synthesis, and uses thereof

The present invention provides novel moenomycin analogs as well as pharmaceutical compositions thereof, methods of synthesis, and methods of use in treating an infection by administering an inventive compound to a subject in need thereof. The moenomycin analogs may be prepared synthetically, biosynthetically, or semi-synthetically. The analogs are particularly useful in treating or preventing infections caused by Gram-positive organisms. Certain inventive compounds may have a broader spectrum of coverage, which includes Gram-negative organisms.

A glycopeptide of the formula A-A-A-A-A-A-A, in which each dash represents a covalent bond; wherein Acomprises a modified or unmodified &#x3b1;-amino acid residue, alkyl, aryl, aralkyl, alkanoyl, aroyl, aralkanoyl, heterocyclic, heterocyclic-carbonyl, heterocyclic-alkyl, heterocyclic-alkyl-carbonyl, alkylsulfonyl, arylsulfonyl, guanidinyl, carbamoyl, or xanthyl; wherein each of Ato Acomprises a modified or unmodified &#x3b1;-amino acid residue, whereby (i) Ais linked to an amino group on A, (ii) each of A, Aand Abears an aromatic side chain, which aromatic side chains are cross-linked together by two or more covalent bonds, and (iii) Abears a terminal carboxyl, ester, amide, or N-substituted amide group; A chemical library comprising a plurality of the glycopeptides of the invention. A method for preparing a glycopeptide by glycosylation of an aglycone derived from a glycopeptide antibiotic. A method for preparing a glycopeptide by preparing a pseudoaglycone from a glycopeptide antibiotic and glycosylating the pseudoaglycone.

Glycopeptide antibiotics, combinatorial libraries of glycopeptide antibiotics and methods of producing same

A method is described for identifying a compound that modulates the ability of a glycosyltransferase to bind a substrate comprising combining a glycosyltransferase, a labeled substrate, and a compound, in a reaction vessel, under conditions known to be suitable for the glycosyltransferase to bind the labeled substrate, measuring an amount of labeled substrate bound to the glycosyltransferase, and comparing the amount to a standardized amount to identify a relative increase or decrease in substrate bound glycosyltransferase, thereby identifying a compound that modulates the ability of the glycosyltransferase to bind the substrate. A composition comprising an effective amount of a compound of Formula I (the substituents of which are described herein), or a stereoisomer, or pharmaceutically acceptable salt thereof, that inhibits the ability of a glycosyltransferase to bind a substrate, in a pharmaceutically acceptable carrier is provided 

Identification of active-site inhibitors of glycosyltransferases using a generalizable high-throughput screen

Methods for preparing a glycopeptide are disclosed. The methods comprise the steps of selecting a protected glycopeptide of the formula A-A-A-A-A-A-A, wherein the groups Ato Acomprise the heptapeptide structure of naturally occurring vancomycin; at least Ais linked to a glycosidic group which has a hexose residue linked to A; and the protected glycopeptide has no free amino or carboxyl groups and has a free primary hydroxyl group only at the 6-position of said hexose residue. The protected glycopeptide is contacted with a compound of the formula ArSOG where Ar is an aryl group and G is a leaving group under conditions effective to allow reaction of said free primary hydroxyl group to form a glycopeptide sulfonate ester; and the glycopeptide sulfonate ester is contacted with a nucleophile under conditions effective to allow displacement of a sulfonate group to produce a substituted glycopeptide.

Glycopeptide antibiotics, combinational libraries of glycopeptide antibiotics and methods of producing same

The present invention relates to vancomycin analogs in which the vancosamine residue is substituted with a lipid-like substituent that includes a first aryl moiety and a second aryl moiety joined together by a flexible linker moiety, that is not a single bond directly joining the first aryl moiety and the second aryl moiety, and a glucose C-6 substituent modified to be other than the naturally occurring hydroxyl group, or pharmaceutically acceptable salts thereof.

Growing community of inventors

Princeton, NJ, United States of America

Daniel E Kahne