University of Illinois

University of California

Eric Oldfield

Yonghui Zhang

Yongcheng Song

John M Sanders

Julian M W Chan

Victor Nizet

George Y Liu

Wei Zhu

Fenglin Yin

Steffen Lindert

William Sinko

Kai Li

James Andrew McCammon

Weixue Wang

Ke Wang

With the rise in resistance to antibiotics such as methicillin, there is a need for new drugs. The invention provides small molecules that inhibit cellular drug targets such as UPPS and FPPS by interacting with binding pockets, thereby preventing enzyme function. Compounds described herein are also active against(MIC90&#x2dc;0.25 &#x3bc;g/mL), can potently synergize with methicillin (fractional inhibitory concentration index=0.25), and are protective in a mouse infection model. The invention therefore provides numerous compounds for anti-bacterial treatments and for restoring sensitivity to drugs such as methicillin, using combination therapies.

Antibacterial compounds targeting isoprenoid biosynthesis

The disclosure provides compounds and methods to treat a microbial or a bacterial pathogenesis, and demonstrates that thepigment is a virulence factor and potential novel target for antimicrobial therapy.

Antimicrobial compositions for treating microbial infections

The invention provides compounds, compositions, and methods for studying the Rohmer pathway and for treating bacterial infections or parasitic infections. The parasitic infection can be a protozoan infection, such as malaria. The compounds and compositions can also be used as antibiotics, for example, to kill bacteria or parasites, or to inhibit bacterial or parasite growth. The invention further provides inhibitors of isoprenoid biosynthesis enzymes, and methods of inhibiting the activity of isoprenoid biosynthesis enzymes. The compounds can be, for example, alkynes or allenes that bind to a unique Fe of an Fe4S4 cluster of an isoprenoid biosynthesis enzyme.

Enzyme inhibiting compounds and methods

The disclosure provides compounds and methods to treat bacterial pathogenesis, and demonstrates that thepigment is a virulence factor and potential novel target for antimicrobial therapy.

Antimicrobial therapy for bacterial infections

Bisphosphonate compounds and related methods of making and using are disclosed, including pyridinium-1-yl, quinolinium-1-yl, and related compounds. The activity of compounds is disclosed in the context of functional assays such asfarnesyl diphosphate synthase (FPPS) inhibition,growth inhibition, human gamma delta T cell activation, and bone resorption. The applicability of bisphosphonate compounds in the context of parasitic infections, for example against trypanosomes, is disclosed. Further potential applications of the invention are disclosed regarding the treatment of one or more conditions such as bone resorption disorders, cancer, bone pain, infectious diseases, and in immunotherapy.

Bisphosphonate compounds and methods for bone resorption diseases, cancer, bone pain, immune disorders, and infectious diseases

The disclosure provides, inter alia, novel bisphosphonate compounds and methods of making and using such compounds. In certain embodiments, compounds of the invention include bisphosphonates that are capable of selectively inhibiting one or more of farnesyl diphosphate synthase (FPPS), geranylgeranyl diphosphate synthase (GGPPS), and decaprenyl pyrophosphate synthase (DPPS). In preferred embodiments, compounds of the invention are capable of selectively inhibiting two or more of FPPS, GGPPS, and DPPS. In embodiments, compounds and methods of the invention demonstrate superior activity levels, such as in the anti-cancer context, immunostimulation context, and other contexts, which in several cases exceed the activity levels of previous generation bisphosphonate drugs by orders of magnitude. In embodiments, the invention provides compounds and methods in connection with research and therapeutic applications, e.g., for tumor or cancer cell growth inhibition, activation of gammadelta T cells, inhibition of certain enzymes related to the mevalonate metabolic pathway, bone resorption diseases, cancer, immune disorders, immunotherapy, and infectious diseases.

Bisphosphonate compounds and methods with enhanced potency for multiple targets including FPPS, GGPPS, and DPPS

The invention provides, inter alia, novel bisphosphonate compounds and methods of making and using. In embodiments, the invention provides compounds and methods in connection with research and therapeutic applications, e.g., for tumor cell growth inhibition, activation of gammadelta T cells, inhibition of farnesyldiphosphate (FPPS) and/or undecaprenyldiphosphate synthase enzymes, bone resorption diseases, cancer, immune disorders, immunotherapy, and infectious diseases. In regards to certain embodiments, a surprising advance has been the recognition that certain structural features can significantly enhance the activity of the compounds. For example, the presence of particular cationic species e.g., phosphonium, sulfonium, and arsonium moieties can contribute to desirable functional activity when positioned near a bisphosphonate moiety. In other embodiments of non-nitrogen containing bisphosphonates, terphenyl and benzyl bisphosphonate compounds and methods are provided. Further variations are also provided.

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Champaign, IL, United States of America

Eric Oldfield