The Texas A&m University System

Leland Stanford Junior University

James C Sacchettini

Nian E Zhou

Deeann Wallis

Billy Fred McCutchen

Dwight Baker

Manchi C M Reddy

Niam Zhou

Steven A Maxwell

Jianghong Rao

Jeffrey D Cirillo

Hexin Xie

Joel S Freundlich

Matthew W Miller

Theresa W Fossum

Thomas R Ioerger

Vijay Gawandi

Inna V Kriger

Steve Maxwell

Compositions and methods for inhibiting and/or sensitizing or re-sensitizing a parasite to an antiparasitic drug are provided. The compositions can comprise a an arylphenoxypropionate derivative, an aryloxyphenoxyacetate derivative, an aryloxyphenylacetate derivative, one or more substituted quinols, or a pharmaceutically acceptable salt, hydrate, or prodrug thereof, or a combination thereof in an amount and formulation sufficient to sensitize the parasite to the drug, treating infection of a patient by a parasite with a drug, or to prevent symptomatic infection of a patient by a parasite with a drug.

Compositions and methods for drug sensitization of parasites

A composition comprising a drug selected from the group consisting of an arylphenoxypropionate derivative, an aryloxyphenoxyacetate derivative, an aryloxyphenylacetate derivative, a substituted quinol, or a salt, hydrate, or prodrugs thereof, or a combination thereof, in an amount and formulation sufficient to inhibit ais disclosed.

Compositions and methods for inhibition of mycobacteria

Compositions and methods for inhibiting and/or sensitizing or re-sensitizing a parasite to an antiparasitic drug are provided. The compositions can comprise a rifamycin derivative or a pharmaceutically acceptable salt, hydrate, or prodrug thereof in an amount and formulation sufficient to inhibit or induce drug-sensitization in a parasite. The methods can comprise administering a rifamycin derivative or a pharmaceutically acceptable salt, hydrate, or prodrug thereof to a parasite in an amount and formulation sufficient to inhibit or induce drug-sensitization in the parasite.

The disclosure provides rifamycin and rifamycin derivative compositions, including rifabutin and rifabutin derivative compositions able to cause drug-sensitization in a cancer cell or inhibition of a cancer cell. The disclosure also provides methods of administering such compositions to cancer cells to sensitize them to drugs, such as chemotherapeutics, or directly inhibit them. The disclosure also provides methods of administering such compositions to increase reactive oxygen species (ROS), particularly superoxides, in cancer cells. The disclosure further provides methods of determining whether a cancer will respond to chemotherapeutics and whether to administer rifamycin or a rifamycin derivative based on ROS levels in cancer cells of a patient.

Compositions and methods for drug-sensitization or inhibition of a cancer cell

&#x3b2;-Lactamase substrates and methods for using the substrates to detect &#x3b2;-lactamase diagnose tuberculosis.

&#x3b2;-lactamase substrates and methods of their use for the diagnosis of tuberculosis

Provided herein are methods for detecting, quantifying, differentiating, diagnosing and imaging pathogenic bacteria or condition associated therewith using substrates for bacterial enzymes. Fluorescent, luminescent or colorimetric signals emitted by substrates or enzyme products in the presence of the bacteria are compared to controls to detect and locate the pathogenic bacteria. Provided is a method for screening therapeutic agents to treat the pathophysiological conditions by measuring a signal emitted from the substrates or products in the presence and absence of the potential therapeutic agent and a diagnostic method for detecting a mycobacterial infection in a subject by contacting biological samples with a substrate and imaging for signals emitted from a mycobacterial beta-lactamase product. Also provided are fluorogenic substrates or substrates comprising a colored dye or a chemical reagent effective to induce a color or pH change.

Use of bacterial beta-lactamase for in vitro diagnostics and in vivo imaging, diagnostics and therapeutics

The present invention provides aryl- or heteroaryl-diketo acid compounds effective to inhibit an activity of a Mycobacterial malate synthase enzyme or to inhibit a malate synthase activity in other bacteria having the enzyme. The compounds may be phenyl- naphthyl-, or thienyl-substituted diketo acids and carboxylate derivatives thereof. Also provided are methods of treating tuberculosis or other pathophysiological conditions associated with a malate synthase enzyme with the inhibitory compounds and methods of in silico design of the inhibitory compounds. In addition, the present invention provides the inhibitory compounds designed by this method. Furthermore, three-dimensional X-ray crystal structures of the Mycobacterial malate synthase complexed with the inhibitory compounds are provided. Further still a method for stabilizing an aromatic or heteroaromatic diketo acid or its prodrug or close analog in solution by derivatizing at least the ortho position on the aromatic ring is provided.

Growing community of inventors

College Station, TX, United States of America

James C Sacchettini