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Dive into the research topics where Michelle M. Butler is active.

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Featured researches published by Michelle M. Butler.


Journal of Virology | 2011

Identification of a Small-Molecule Entry Inhibitor for Filoviruses

Arnab Basu; Bing Li; Debra M. Mills; Rekha G. Panchal; Steven C. Cardinale; Michelle M. Butler; Norton P. Peet; Helena Majgier-Baranowska; John D. Williams; Ishan Patel; Donald T. Moir; Sina Bavari; Ranjit Ray; Michael Farzan; Lijun Rong; Terry L. Bowlin

ABSTRACT Ebola virus (EBOV) causes severe hemorrhagic fever, for which therapeutic options are not available. Preventing the entry of EBOV into host cells is an attractive antiviral strategy, which has been validated for HIV by the FDA approval of the anti-HIV drug enfuvirtide. To identify inhibitors of EBOV entry, the EBOV envelope glycoprotein (EBOV-GP) gene was used to generate pseudotype viruses for screening of chemical libraries. A benzodiazepine derivative (compound 7) was identified from a high-throughput screen (HTS) of small-molecule compound libraries utilizing the pseudotype virus. Compound 7 was validated as an inhibitor of infectious EBOV and Marburg virus (MARV) in cell-based assays, with 50% inhibitory concentrations (IC50s) of 10 μM and 12 μM, respectively. Time-of-addition and binding studies suggested that compound 7 binds to EBOV-GP at an early stage during EBOV infection. Preliminary Schrödinger SiteMap calculations, using a published EBOV-GP crystal structure in its prefusion conformation, suggested a hydrophobic pocket at or near the GP1 and GP2 interface as a suitable site for compound 7 binding. This prediction was supported by mutational analysis implying that residues Asn69, Leu70, Leu184, Ile185, Leu186, Lys190, and Lys191 are critical for the binding of compound 7 and its analogs with EBOV-GP. We hypothesize that compound 7 binds to this hydrophobic pocket and as a consequence inhibits EBOV infection of cells, but the details of the mechanism remain to be determined. In summary, we have identified a novel series of benzodiazepine compounds that are suitable for optimization as potential inhibitors of filoviral infection.


Antimicrobial Agents and Chemotherapy | 2007

Antibacterial Activity and Mechanism of Action of a Novel Anilinouracil-Fluoroquinolone Hybrid Compound

Michelle M. Butler; William A. LaMarr; Kimberly A. Foster; Marjorie H. Barnes; Donna J. Skow; Patrick T. Lyden; Lauren M. Kustigian; Chengxin Zhi; Neal C. Brown; George E. Wright; Terry L. Bowlin

ABSTRACT The anilinouracils (AUs) such as 6-(3-ethyl-4-methylanilino)uracil (EMAU) are a novel class of gram-positive, selective, bactericidal antibacterials which inhibit pol IIIC, the gram-positive-specific replicative DNA polymerase. We have linked various fluoroquinolones (FQs) to the N-3 position of EMAU to generate a variety of AU-FQ “hybrids” offering the potential for targeting two distinct steps in DNA replication. In this study, the properties of a hybrid, “251D,” were compared with those of representative AUs and FQs in a variety of in vitro assays, including pol IIIC and topoisomerase/gyrase enzyme assays, antibacterial, bactericidal, and mammalian cytotoxicity assays. Compound 251D potently inhibited pol IIIC and topoisomerase/gyrase, displayed gram-positive antibacterial potency at least 15 times that of the corresponding AU compound, and as expected, acted selectively on bacterial DNA synthesis. Compound 251D was active against a broad panel of antibiotic-resistant gram-positive pathogens as well as several gram-negative organisms and was also active against both AU- and FQ-resistant gram-positive organisms, demonstrating its capacity for attacking both of its potential targets in the bacterium. 251D also was bactericidal for gram-positive organisms and lacked toxicity in vitro. Although we obtained strains of Staphylococcus aureus resistant to the individual parent compounds, spontaneous resistance to 251D was not observed. We obtained 251D resistance in multiple-passage experiments, but resistance developed at a pace comparable to those for the parent compounds. This class of AU-FQ hybrids provides a promising new pharmacophore with an unusual dual mechanism of action and potent activity against antibiotic-sensitive and -resistant gram-positive pathogens.


Molecular Pharmacology | 2012

Solute Restriction Reveals an Essential Role for clag3-Associated Channels in Malaria Parasite Nutrient Acquisition

Ajay D. Pillai; Wang Nguitragool; Brian Lyko; Keithlee Dolinta; Michelle M. Butler; Son T. Nguyen; Norton P. Peet; Terry L. Bowlin; Sanjay A. Desai

The plasmodial surface anion channel (PSAC) increases erythrocyte permeability to many solutes in malaria but has uncertain physiological significance. We used a PSAC inhibitor with different efficacies against channels from two Plasmodium falciparum parasite lines and found concordant effects on transport and in vitro parasite growth when external nutrient concentrations were reduced. Linkage analysis using this growth inhibition phenotype in the Dd2 × HB3 genetic cross mapped the clag3 genomic locus, consistent with a role for two clag3 genes in PSAC-mediated transport. Altered inhibitor efficacy, achieved through allelic exchange or expression switching between the clag3 genes, indicated that the inhibitor kills parasites through direct action on PSAC. In a parasite unable to undergo expression switching, the inhibitor selected for ectopic homologous recombination between the clag3 genes to increase the diversity of available channel isoforms. Broad-spectrum inhibitors, which presumably interact with conserved sites on the channel, also exhibited improved efficacy with nutrient restriction. These findings indicate that PSAC functions in nutrient acquisition for intracellular parasites. Although key questions regarding the channel and its biological role remain, antimalarial drug development targeting PSAC should be pursued.


Journal of Medicinal Chemistry | 2010

Synthesis and Biological Evaluation of Botulinum Neurotoxin A Protease Inhibitors

Bing Li; Ramdas Pai; Steven C. Cardinale; Michelle M. Butler; Norton P. Peet; Donald T. Moir; Sina Bavari; Terry L. Bowlin

NSC 240898 was previously identified as a botulinum neurotoxin A light chain (BoNT/A LC) endopeptidase inhibitor by screening the National Cancer Institute Open Repository diversity set. Two types of analogues have been synthesized and shown to inhibit BoNT/A LC in a FRET-based enzyme assay, with confirmation in an HPLC-based assay. These two series of compounds have also been evaluated for inhibition of anthrax lethal factor (LF), an unrelated metalloprotease, to examine enzyme specificity of the BoNT/A LC inhibition. The most potent inhibitor against BoNT/A LC in these two series is compound 12 (IC(50) = 2.5 microM, FRET assay), which is 4.4-fold more potent than the lead structure and 11.2-fold more selective for BoNT/A LC versus the anthrax LF metalloproteinase. Structure-activity relationship studies have revealed structural features important to potency and enzyme specificity.


Antimicrobial Agents and Chemotherapy | 2009

Novel Broad-Spectrum Bis-(Imidazolinylindole) Derivatives with Potent Antibacterial Activities against Antibiotic-Resistant Strains

Rekha G. Panchal; Ricky L. Ulrich; Douglas Lane; Michelle M. Butler; Timothy J. Opperman; John D. Williams; Norton P. Peet; Donald T. Moir; Tam Luong Nguyen; Rick Gussio; Terry L. Bowlin; Sina Bavari

ABSTRACT Given the limited number of structural classes of clinically available antimicrobial drugs, the discovery of antibacterials with novel chemical scaffolds is an important strategy in the development of effective therapeutics for both naturally occurring and engineered resistant strains of pathogenic bacteria. In this study, several diarylamidine derivatives were evaluated for their ability to protect macrophages from cell death following infection with Bacillus anthracis, a gram-positive spore-forming bacterium. Four bis-(imidazolinylindole) compounds were identified with potent antibacterial activity as measured by the protection of macrophages and by the inhibition of bacterial growth in vitro. These compounds were effective against a broad range of gram-positive and gram-negative bacterial species, including several antibiotic-resistant strains. Minor structural variations among the four compounds correlated with differences in their effects on bacterial macromolecular synthesis and mechanisms of resistance. In vivo studies revealed protection by two of the compounds of mice lethally infected with B. anthracis, Staphylococcus aureus, or Yersinia pestis. Taken together, these results indicate that the bis-(imidazolinylindole) compounds represent a new chemotype for the development of therapeutics for both gram-positive and gram-negative bacterial species as well as against antibiotic-resistant infections.


Journal of Medicinal Chemistry | 2012

Coumarin-based inhibitors of Bacillus anthracis and Staphylococcus aureus replicative DNA helicase: chemical optimization, biological evaluation, and antibacterial activities.

Bing Li; Ramdas Pai; Ming Di; Daniel Aiello; Marjorie H. Barnes; Michelle M. Butler; Tommy F. Tashjian; Norton P. Peet; Terry L. Bowlin; Donald T. Moir

The increasing prevalence of drug-resistant bacterial infections demands the development of new antibacterials that are not subject to existing mechanisms of resistance. Previously, we described coumarin-based inhibitors of an underexploited bacterial target, namely the replicative helicase. Here we report the synthesis and evaluation of optimized coumarin-based inhibitors with 9-18-fold increased potency against Staphylococcus aureus (Sa) and Bacillus anthracis (Ba) helicases. Compounds 20 and 22 provided the best potency, with IC(50) values of 3 and 1 μM, respectively, against the DNA duplex strand-unwinding activities of both B. anthracis and S. aureus helicases without affecting the single strand DNA-stimulated ATPase activity. Selectivity index (SI = CC(50)/MIC) values against S. aureus and B. anthracis for compound 20 were 33 and 66 and for compound 22 were 20 and 40, respectively. In addition, compounds 20 and 22 demonstrated potent antibacterial activity against multiple ciprofloxacin-resistant MRSA strains, with MIC values ranging between 0.5 and 4.2 μg/mL.


Molecules | 2010

Small Molecule Inhibitors as Countermeasures for Botulinum Neurotoxin Intoxication

Bing Li; Norton P. Peet; Michelle M. Butler; James C. Burnett; Donald T. Moir; Terry L. Bowlin

Botulinum neurotoxins (BoNTs) are the most potent of known toxins and are listed as category A biothreat agents by the U.S. CDC. The BoNT-mediated proteolysis of SNARE proteins inhibits the exocytosis of acetylcholine into neuromuscular junctions, leading to life-threatening flaccid paralysis. Currently, the only therapy for BoNT intoxication (which results in the disease state botulism) includes experimental preventative antibodies and long-term supportive care. Therefore, there is an urgent need to identify and develop inhibitors that will serve as both prophylactic agents and post-exposure ‘rescue’ therapeutics. This review focuses on recent progress to discover and develop small molecule inhibitors as therapeutic countermeasures for BoNT intoxication.


Current Opinion in Pharmacology | 2012

New classes of antibiotics.

Donald T. Moir; Timothy J. Opperman; Michelle M. Butler; Terry L. Bowlin

Several novel chemical classes of antibiotics are currently in human clinical studies. While most are narrow spectrum agents that inhibit unexploited targets, the susceptible pathogens are clinically important, including staphylococci, pseudomonads, and mycobacteria. Given the paucity of antibacterial agents consisting of novel chemical scaffolds that act on established targets, these new antibacterial scaffolds, which are active against new targets, represent an important advance in the battle against antibiotic resistance. Indeed, most of these compounds are unlikely to be subject to existing compound-based or target-based resistance mechanisms.


Antimicrobial Agents and Chemotherapy | 2010

Comparative in vitro activity profiles of novel bis-indole antibacterials against gram-positive and gram-negative clinical isolates.

Michelle M. Butler; John D. Williams; Norton P. Peet; Donald T. Moir; Rekha G. Panchal; Sina Bavari; Dean L. Shinabarger; Terry L. Bowlin

ABSTRACT Antimicrobial susceptibilities of 233 Gram-positive and 180 Gram-negative strains to two novel bis-indoles were evaluated. Both compounds were potent inhibitors of Gram-positive bacteria, with MIC90 values of 0.004 to 0.5 μg/ml. One bis-indole, MBX 1162, exhibited potent activity against all Gram-negative strains, with MIC90 values of 0.12 to 4 μg/ml, even against high-level-resistant pathogens, and compared favorably to all comparator antibiotics. The bis-indole compounds show promise for the treatment of multidrug-resistant clinical pathogens.


Antimicrobial Agents and Chemotherapy | 2012

MBX-500, a Hybrid Antibiotic with In Vitro and In Vivo Efficacy against Toxigenic Clostridium difficile

Michelle M. Butler; Dean L. Shinabarger; Diane M. Citron; Ciaran P. Kelly; Sofya Dvoskin; George E. Wright; Hanping Feng; Saul Tzipori; Terry L. Bowlin

ABSTRACT Clostridium difficile infection (CDI) causes moderate to severe disease, resulting in diarrhea and pseudomembranous colitis. CDI is difficult to treat due to production of inflammation-inducing toxins, resistance development, and high probability of recurrence. Only two antibiotics are approved for the treatment of CDI, and the pipeline for therapeutic agents contains few new drugs. MBX-500 is a hybrid antibacterial, composed of an anilinouracil DNA polymerase inhibitor linked to a fluoroquinolone DNA gyrase/topoisomerase inhibitor, with potential as a new therapeutic for CDI treatment. Since MBX-500 inhibits three bacterial targets, it has been previously shown to be minimally susceptible to resistance development. In the present study, the in vitro and in vivo efficacies of MBX-500 were explored against the Gram-positive anaerobe, C. difficile. MBX-500 displayed potency across nearly 50 isolates, including those of the fluoroquinolone-resistant, toxin-overproducing NAP1/027 ribotype, performing as well as comparator antibiotics vancomycin and metronidazole. Furthermore, MBX-500 was a narrow-spectrum agent, displaying poor activity against many other gut anaerobes. MBX-500 was active in acute and recurrent infections in a toxigenic hamster model of CDI, exhibiting full protection against acute infections and prevention of recurrence in 70% of the animals. Hamsters treated with MBX-500 displayed significantly greater weight gain than did those treated with vancomycin. Finally, MBX-500 was efficacious in a murine model of CDI, again demonstrating a fully protective effect and permitting near-normal weight gain in the treated animals. These selective anti-CDI features support the further development of MBX 500 for the treatment of CDI.

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George E. Wright

National Institutes of Health

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Neal C. Brown

University of Massachusetts Medical School

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Sina Bavari

University of Pittsburgh

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Marjorie H. Barnes

University of Massachusetts Medical School

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Rekha G. Panchal

United States Army Medical Research Institute of Infectious Diseases

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Kimberly A. Foster

University of Massachusetts Medical School

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Ramdas Pai

University of Minnesota

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