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1. Protection of hamsters from mortality by reducing fecal moxifloxacin concentration with DAV131A in a model of moxifloxacin-induced Clostridium difficile colitis

Author

Burdet, Charles, Sayah-Jeanne, Sakina, Nguyen, Thu Thuy, Miossec, Christine, Saint-Lu, Nathalie, Pulse, Mark, Weiss, William, Andremont, Antoine, Mentré, France, and De Gunzburg, Jean

Subjects
Quantitative Biology - Quantitative Methods
Abstract

BackgroundLowering the gut exposure to antibiotics during treatments can prevent microbiota disruption. We evaluated the effect of an activated charcoal-based adsorbent, DAV131A, on fecal free moxifloxacin concentration and mortality in a hamster model of moxifloxacin-induced C. difficile infection.Methods215 hamsters receiving moxifloxacin subcutaneously (D1-D5) were orally infected at D3 with C. difficile spores. They received various doses (0-1800mg/kg/day) and schedules (BID, TID) of DAV131A (D1-D8). Moxifloxacin concentration and C. difficile counts were determined at D3, and mortality at D12. We compared mortality, moxifloxacin concentration and C. difficile counts according to DAV131A regimens, and modelled the link between DAV131A regimen, moxifloxacin concentration and mortality. ResultsAll hamsters that received no DAV131A died, but none of those that received 1800mg/kg/day. A significant dose-dependent relationship between DAV131A dose and (i) mortality rates, (ii) moxifloxacin concentration and (iii) C. difficile counts was evidenced. Mathematical modeling suggested that (i) lowering moxifloxacin concentration at D3, which was 58$\mu$g/g (95%CI=50-66) without DAV131A, to 17$\mu$g/g (14-21) would reduce mortality by 90% and (ii) this would be achieved with a daily DAV131A dose of 703mg/kg (596-809).ConclusionsIn this model of C. difficile infection, DAV131A reduced mortality in a dose-dependent manner by decreasing fecal free moxifloxacin concentration.

Published
2017
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2. Can Ceftazidime-Avibactam and Aztreonam Overcome β-Lactam Resistance Conferred by Metallo-β-Lactamases in Enterobacteriaceae?

Author

Marshall, Steven, Hujer, Andrea M, Rojas, Laura J, Papp-Wallace, Krisztina M, Humphries, Romney M, Spellberg, Brad, Hujer, Kristine M, Marshall, Emma K, Rudin, Susan D, Perez, Federico, Wilson, Brigid M, Wasserman, Ronald B, Chikowski, Linda, Paterson, David L, Vila, Alejandro J, van Duin, David, Kreiswirth, Barry N, Chambers, Henry F, Fowler, Vance G, Jacobs, Michael R, Pulse, Mark E, Weiss, William J, and Bonomo, Robert A

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Microbiology, Clinical Sciences, Medical Microbiology, Infectious Diseases, Antimicrobial Resistance, Vaccine Related, Emerging Infectious Diseases, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Infection, Animals, Anti-Bacterial Agents, Azabicyclo Compounds, Aztreonam, Ceftazidime, Colony Count, Microbial, Cyclophosphamide, Drug Administration Schedule, Drug Combinations, Drug Therapy, Combination, Enterobacteriaceae, Enterobacteriaceae Infections, Female, Gene Expression, Humans, Klebsiella Infections, Klebsiella pneumoniae, Mice, Microbial Sensitivity Tests, Neutropenia, Plasmids, Soft Tissue Infections, Thigh, beta-Lactam Resistance, beta-Lactamases, ceftazidime, avibactam, aztreonam, disk diffusion, metallo-beta-lactamases, metallo-β-lactamases, Pharmacology and Pharmaceutical Sciences, Medical microbiology, Pharmacology and pharmaceutical sciences
Abstract

Based upon knowledge of the hydrolytic profile of major β-lactamases found in Gram-negative bacteria, we tested the efficacy of the combination of ceftazidime-avibactam (CAZ-AVI) with aztreonam (ATM) against carbapenem-resistant enteric bacteria possessing metallo-β-lactamases (MBLs). Disk diffusion and agar-based antimicrobial susceptibility testing were initially performed to determine the in vitro efficacy of a unique combination of CAZ-AVI and ATM against 21 representative Enterobacteriaceae isolates with a complex molecular background that included blaIMP, blaNDM, blaOXA-48, blaCTX-M, blaAmpC, and combinations thereof. Time-kill assays were conducted, and the in vivo efficacy of this combination was assessed in a murine neutropenic thigh infection model. By disk diffusion assay, all 21 isolates were resistant to CAZ-AVI alone, and 19/21 were resistant to ATM. The in vitro activity of CAZ-AVI in combination with ATM against diverse Enterobacteriaceae possessing MBLs was demonstrated in 17/21 isolates, where the zone of inhibition was ≥21 mm. All isolates demonstrated a reduction in CAZ-AVI agar dilution MICs with the addition of ATM. At 2 h, time-kill assays demonstrated a ≥4-log10-CFU decrease for all groups that had CAZ-AVI with ATM (8 μg/ml) added, compared to the group treated with CAZ-AVI alone. In the murine neutropenic thigh infection model, an almost 4-log10-CFU reduction was noted at 24 h for CAZ-AVI (32 mg/kg every 8 h [q8h]) plus ATM (32 mg/kg q8h) versus CAZ-AVI (32 mg/kg q8h) alone. The data presented herein require us to carefully consider this new therapeutic combination to treat infections caused by MBL-producing Enterobacteriaceae.

Published
2017

3. Surgical Primary Tumor Resection Reduces Accumulation of CD11b+ Myeloid Cells in the Lungs Augmenting the Efficacy of an Intranasal Cancer Vaccination against Secondary Lung Metastasis

Author

Donkor, Michael, primary, Choe, Jamie Y., additional, Reid, Danielle Marie, additional, Fiadjoe, Hope K., additional, Quinn, Byron, additional, Ranjan, Amalendu, additional, Pulse, Mark, additional, Chaudhary, Pankaj, additional, Basha, Riyaz, additional, and Jones, Harlan P., additional

Published
2023
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4. An mRNA-based platform for the delivery of pathogen-specific IgA into mucosal secretions

Author

Deal, Cailin E., primary, Richards, Angelene F., additional, Yeung, Tracy, additional, Maron, Max J., additional, Wang, Ziqiu, additional, Lai, Yen-Ting, additional, Fritz, Brian R., additional, Himansu, Sunny, additional, Narayanan, Elisabeth, additional, Liu, Ding, additional, Koleva, Rositsa, additional, Licht, Stuart, additional, Hsiao, Chiaowen J., additional, Rajlic, Ivana L., additional, Koch, Hillary, additional, Kleyman, Michael, additional, Pulse, Mark E., additional, Weiss, William J., additional, Doering, Jennifer E., additional, Lindberg, Samantha K., additional, Mantis, Nicholas J., additional, Carfi, Andrea, additional, and Plante, Obadiah J., additional

Published
2023
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6. Surgical Primary Tumor Resection Reduces Accumulation of CD11b + Myeloid Cells in the Lungs Augmenting the Efficacy of an Intranasal Cancer Vaccination against Secondary Lung Metastasis.

Author

Donkor, Michael, Choe, Jamie Y., Reid, Danielle Marie, Fiadjoe, Hope K., Quinn, Byron, Ranjan, Amalendu, Pulse, Mark, Chaudhary, Pankaj, Basha, Riyaz, and Jones, Harlan P.

Subjects
LUNGS, TUMOR surgery, MYELOID cells, CANCER vaccines, INTRANASAL administration, LUNG surgery, TUMOR suppressor genes, PROGRAMMED cell death 1 receptors
Abstract

A hallmark of effective cancer treatment is the prevention of tumor reoccurrence and metastasis to distal organs, which are responsible for most cancer deaths. However, primary tumor resection is expected to be curative as most solid tumors have been shown both experimentally and clinically to accelerate metastasis to distal organs including the lungs. In this study, we evaluated the efficacy of our engineered nasal nano-vaccine (CpG-NP-Tag) in reducing accelerated lung metastasis resulting from primary tumor resection. Cytosine–phosphate–guanine oligonucleotide [CpG ODN]-conjugated nanoparticle [NP] encapsulating tumor antigen [Tag] (CpG-NP-Tag) was manufactured and tested in vivo using a syngeneic mouse mammary tumor model following intranasal delivery. We found that our nasal nano-vaccine (CpG-NP-Tag), compared to control NPs administered after primary mammary tumor resection, significantly reduced lung metastasis in female BALB/c mice subjected to surgery (surgery mice). An evaluation of vaccine efficacy in both surgery and non-surgery mice revealed that primary tumor resection reduces CD11b+ monocyte-derived suppressor-like cell accumulation in the lungs, allowing increased infiltration of vaccine-elicited T cells (IFN-γ CD8+ T cells) in the lungs of surgery mice compared to non-surgery mice. These findings suggest that the combination of the target delivery of a nasal vaccine in conjunction with the standard surgery of primary tumors is a plausible adjunctive treatment against the establishment of lung metastasis. [ABSTRACT FROM AUTHOR]

Published
2024
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8. mRNA delivery of dimeric human IgA protects mucosal tissues from bacterial infection

Author

Deal, Cailin E., primary, Richards, Angelene F., additional, Yeung, Tracy, additional, Maron, Max J., additional, Wang, Ziqiu, additional, Lai, Yen-Ting, additional, Fritz, Brian R., additional, Himansu, Sunny, additional, Narayanan, Elisabeth, additional, Liu, Ding, additional, Koleva, Rositsa, additional, Licht, Stuart, additional, Hsiao, Chiaowen J., additional, Rajlic, Ivana L., additional, Koch, Hillary, additional, Kleyman, Michael, additional, Pulse, Mark E., additional, Weiss, William J., additional, Doering, Jennifer E., additional, Lindberg, Samantha K., additional, Mantis, Nicholas J., additional, Carfi, Andrea, additional, and Plante, Obadiah J., additional

Published
2023
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9. An mRNA-Based Platform for the Delivery of Pathogen-Specific IgA into Mucosal Secretions

Author

Deal, Cailin, primary, Richards, Angelene F., additional, Yeung, Tracy, additional, Maron, Max J., additional, Wang, Ziqiu, additional, Lai, Yen-Ting, additional, Fritz, Brian R., additional, Himansu, Sunny, additional, Narayanan, Elisabeth, additional, Liu, Ding, additional, Koleva, Rositsa, additional, Licht, Stuart, additional, Hsiao, Chiaowen J., additional, Rajlic, Ivana L., additional, Koch, Hillary, additional, Kleyman, Michael, additional, Pulse, Mark E., additional, Weiss, William J., additional, Doering, Jennifer E., additional, Lindberg, Samantha K., additional, Mantis, Nicholas, additional, Carfi, Andrea, additional, and Plante, Obadiah J., additional

Published
2023
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12. Design, Synthesis, and Characterization of TNP-2198, a Dual-Targeted Rifamycin-Nitroimidazole Conjugate with Potent Activity against Microaerophilic and Anaerobic Bacterial Pathogens

Author

Ma, Zhenkun, primary, He, Shijie, additional, Yuan, Ying, additional, Zhuang, Zhijun, additional, Liu, Yu, additional, Wang, Huan, additional, Chen, Jing, additional, Xu, Xiangyi, additional, Ding, Charles, additional, Molodtsov, Vadim, additional, Lin, Wei, additional, Robertson, Gregory T., additional, Weiss, William J., additional, Pulse, Mark, additional, Nguyen, Phung, additional, Duncan, Leonard, additional, Doyle, Timothy, additional, Ebright, Richard H., additional, and Lynch, Anthony Simon, additional

Published
2022
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14. Microbiological Characterization of VNRX-5236, a Broad-Spectrum β-Lactamase Inhibitor for Rescue of the Orally Bioavailable Cephalosporin Ceftibuten as a Carbapenem-Sparing Agent against Strains of Enterobacterales Expressing Extended-Spectrum β-Lactamases and Serine Carbapenemases

Author

Chatwin, Cassandra L., primary, Hamrick, Jodie C., additional, Trout, Robert E. L., additional, Myers, Cullen L., additional, Cusick, Susan M., additional, Weiss, William J., additional, Pulse, Mark E., additional, Xerri, Luigi, additional, Burns, Christopher J., additional, Moeck, Gregory, additional, Daigle, Denis M., additional, John, Kaitlyn, additional, Uehara, Tsuyoshi, additional, and Pevear, Daniel C., additional

Published
2021
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15. Discovery of VNRX-7145 (VNRX-5236 Etzadroxil): An Orally Bioavailable β-Lactamase Inhibitor for Enterobacterales Expressing Ambler Class A, C, and D Enzymes

Author

Trout, Robert E., primary, Zulli, Allison, additional, Mesaros, Eugen, additional, Jackson, Randy W., additional, Boyd, Steven, additional, Liu, Bin, additional, Hamrick, Jodie, additional, Daigle, Denis, additional, Chatwin, Cassandra L., additional, John, Kaitlyn, additional, McLaughlin, Lisa, additional, Cusick, Susan M., additional, Weiss, William J., additional, Pulse, Mark E., additional, Pevear, Daniel C., additional, Moeck, Greg, additional, Xerri, Luigi, additional, and Burns, Christopher J., additional

Published
2021
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17. 1272. Efficacy of a Non-Peptide, Small Molecule Mimic of Host Defense Proteins in Mouse Models of Disseminated Candidiasis and Aspergillosis

Author

Scott, Richard W, primary, Baugh, Simon D P, additional, Freeman, Katie B, additional, Weaver, Damian G, additional, Chaly, Anna L, additional, Whitman, David B, additional, Thanna, Sandeep, additional, Diamond, Gill, additional, Nguyen, Phung, additional, Deviney, Ashley, additional, Weiss, William J, additional, Pulse, Mark E, additional, and Reitz, Allen B, additional

Published
2020
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18. Design, Synthesis, and Characterization of TNP-2198, a Dual-Targeted Rifamycin-Nitroimidazole Conjugate with Potent Activity against Microaerophilic and Anaerobic Bacterial Pathogens.

Author

Zhenkun Ma, Shijie He, Ying Yuan, Zhijun Zhuang, Yu Liu, Huan Wang, Jing Chen, Xiangyi Xu, Charles Ding, Molodtsov, Vadim, Wei Lin, Robertson, Gregory T., Weiss, William J., Pulse, Mark, Phung Nguyen, Duncan, Leonard, Doyle, Timothy, Ebright, Richard H., and Lynch, Anthony Simon

Published
2022
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22. Treatment and Prevention of Recurrent Clostridium difficile Infection with Functionalized Bovine Antibody-Enriched Whey in a Hamster Primary Infection Model

Author

Heidebrecht, Hans-Jürgen, Weiss, William J, Pulse, Mark, Lange, Anton, Gisch, Karina, Kliem, Heike, Mann, Sacha, Pfaffl, Michael W., Kulozik, Ulrich, and Eichel-Streiber, Christoph von

Subjects
Male, prevention of recurrence, hamster model of CDI, Clostridium difficile infection, bovine milk, lcsh:R, Bacterial Toxins, lcsh:Medicine, Antibodies, Article, Disease Models, Animal, Enterotoxins, Milk, Whey Proteins, Bacterial Proteins, Pregnancy, Cricetinae, Bacterial Vaccines, Clostridium Infections, Animals, Cattle, Female, sIgA
Abstract

Toxin-induced Clostridium difficile infection (CDI) is a major disease characterized by severe diarrhea and high morbidity rates. The aim with this study was to develop an alternative drug for the treatment of CDI. Cows were repeatedly immunized to establish specific immunoglobulin G and A titers against toxins A (TcdA) and B (TcdB) and against C. difficile cells in mature milk or colostrum. The effect of three different concentrations of anti-C. difficile whey protein isolates (anti-CD-WPI) and the standard of care antibiotic vancomycin were investigated in an animal model of CD infected hamsters (6 groups, with 10 hamsters each). WPI obtained from the milk of exactly the same cows pre-immunization and a vehicle group served as negative controls. The survival of hamsters receiving anti-CD-WPI was 50, 80 and 100% compared to 10 and 0% for the control groups, respectively. Vancomycin suppressed the growth of C. difficile and thus protected the hamsters at the time of administration, but 90% of these hamsters nevertheless died shortly after discontinuation of treatment. In contrast, the surviving hamsters of the anti-CD-WPI groups survived the entire study period, although they were treated for only 75 h. The specific antibodies not only inactivated the toxins for initial suppression of CDI, but also provoked the inhibition of C. difficile growth after discontinuation, thus preventing recurrence. Oral administration of anti-CD-WPI is a functional therapy of CDI in infected hamsters for both primary treatment and prevention of recurrence. Thus, anti-CD-WPI could address the urgent unmet medical need for treating and preventing recurrent CDI in humans.

Published
2018

23. DAV131A Protects Hamsters from Lethal Clostridioides difficile Infection Induced by Fluoroquinolones

Author

Saint-Lu, Nathalie, primary, Burdet, Charles, additional, Sablier-Gallis, Frédérique, additional, Corbel, Tanguy, additional, Nevière, Agathe, additional, Sayah-Jeanne, Sakina, additional, Pulse, Mark, additional, Weiss, William, additional, Ferreira, Stéphanie, additional, Andremont, Antoine, additional, Mentré, France, additional, and de Gunzburg, Jean, additional

Published
2019
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25. Primary care clinics can be a source of exposure to virulent Clostridium (now Clostridioides) difficile: An environmental screening study of hospitals and clinics in Dallas-Fort Worth region

Author

Simecka, Jerry W., primary, Fulda, Kimberly G., additional, Pulse, Mark, additional, Lee, Joon-hak, additional, Vitucci, John, additional, Nguyen, Phung, additional, Taylor, Patricia, additional, Filipetto, Frank, additional, Espinoza, Anna M., additional, and Sharma, Sushma, additional

Published
2019
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27. Treatment and Prevention of Recurrent Clostridium difficile Infection with Functionalized Bovine Antibody-Enriched Whey in a Hamster Primary Infection Model

Author

Heidebrecht, Hans-Jürgen, primary, Weiss, William J, additional, Pulse, Mark, additional, Lange, Anton, additional, Gisch, Karina, additional, Kliem, Heike, additional, Mann, Sacha, additional, Pfaffl, Michael W., additional, Kulozik, Ulrich, additional, and von Eichel-Streiber, Christoph, additional

Published
2019
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29. Antibiotic-Induced Dysbiosis Predicts Mortality in an Animal Model of Clostridium difficile Infection

Author

Burdet, Charles, primary, Sayah-Jeanne, Sakina, additional, Nguyen, Thu Thuy, additional, Hugon, Perrine, additional, Sablier-Gallis, Frédérique, additional, Saint-Lu, Nathalie, additional, Corbel, Tanguy, additional, Ferreira, Stéphanie, additional, Pulse, Mark, additional, Weiss, William, additional, Andremont, Antoine, additional, Mentré, France, additional, and de Gunzburg, Jean, additional

Published
2018
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31. Antibiotic-induced dysbiosis predicts mortality in an animal model ofClostridium difficileinfection

Author

Burdet, Charles, primary, Sayah-Jeanne, Sakina, additional, Nguyen, Thu Thuy, additional, Hugon, Perrine, additional, Sablier-Gallis, Frédérique, additional, Saint-Lu, Nathalie, additional, Corbel, Tanguy, additional, Ferreira, Stéphanie, additional, Pulse, Mark, additional, Weiss, William, additional, Andremont, Antoine, additional, Mentré, France, additional, and Gunzburg, Jean de, additional

Published
2018
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35. Protection of Hamsters from Mortality by Reducing Fecal Moxifloxacin Concentration with DAV131A in a Model of Moxifloxacin-Induced Clostridium difficile Colitis

Author

Burdet, Charles, primary, Sayah-Jeanne, Sakina, additional, Nguyen, Thu Thuy, additional, Miossec, Christine, additional, Saint-Lu, Nathalie, additional, Pulse, Mark, additional, Weiss, William, additional, Andremont, Antoine, additional, Mentré, France, additional, and de Gunzburg, Jean, additional

Published
2017
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Author

Marshall, Steven, Marshall, Steven, Hujer, Andrea M, Rojas, Laura J, Papp-Wallace, Krisztina M, Humphries, Romney M, Spellberg, Brad, Hujer, Kristine M, Marshall, Emma K, Rudin, Susan D, Perez, Federico, Wilson, Brigid M, Wasserman, Ronald B, Chikowski, Linda, Paterson, David L, Vila, Alejandro J, van Duin, David, Kreiswirth, Barry N, Chambers, Henry F, Fowler, Vance G, Jacobs, Michael R, Pulse, Mark E, Weiss, William J, Bonomo, Robert A, Marshall, Steven, Marshall, Steven, Hujer, Andrea M, Rojas, Laura J, Papp-Wallace, Krisztina M, Humphries, Romney M, Spellberg, Brad, Hujer, Kristine M, Marshall, Emma K, Rudin, Susan D, Perez, Federico, Wilson, Brigid M, Wasserman, Ronald B, Chikowski, Linda, Paterson, David L, Vila, Alejandro J, van Duin, David, Kreiswirth, Barry N, Chambers, Henry F, Fowler, Vance G, Jacobs, Michael R, Pulse, Mark E, Weiss, William J, and Bonomo, Robert A

Published
2017

37. DAV132, an Adsorbent-Based Product, Protects the Gut Microbiome and Prevents Clostridium difficile Infections During Moxifloxacin Treatments

Author

Gunzburg, Jean De, primary, Ghozlane, Amine, additional, Ducher, Annie, additional, Duval, Xavier, additional, Ruppé, Etienne, additional, Pulse, Mark, additional, Chilton, Caroline, additional, Armand-Lefevre, Laurence, additional, Chachaty, Elisabeth, additional, Sayah-Jeanne, Sakina, additional, Doré, Joël, additional, Chatelier, Emmanuelle Le, additional, Levenez, Florence, additional, Kennedy, Sean, additional, Pons, Nicolas, additional, Weiss, William, additional, Wilcox, Mark, additional, Mentré, France, additional, Andremont, Antoine, additional, and Ehrlich, Stanislav Dusko, additional

Published
2015
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42. Small Molecule Inhibitors of Staphylococcus aureus RnpA Alter Cellular mRNA Turnover, Exhibit Antimicrobial Activity, and Attenuate Pathogenesis

Author

Olson, Patrick D., primary, Kuechenmeister, Lisa J., additional, Anderson, Kelsi L., additional, Daily, Sonja, additional, Beenken, Karen E., additional, Roux, Christelle M., additional, Reniere, Michelle L., additional, Lewis, Tami L., additional, Weiss, William J., additional, Pulse, Mark, additional, Nguyen, Phung, additional, Simecka, Jerry W., additional, Morrison, John M., additional, Sayood, Khalid, additional, Asojo, Oluwatoyin A., additional, Smeltzer, Mark S., additional, Skaar, Eric P., additional, and Dunman, Paul M., additional

Published
2011
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45. In VivoAssessment of SMT19969 in a Hamster Model of Clostridium difficileInfection

Author

Weiss, William, Pulse, Mark, and Vickers, Richard

Abstract

ABSTRACTSMT19969 [2,2′-bis(4-pyridyl)3H,3′-H5,5-bibenzimidazole] is a novel narrow-spectrum nonabsorbable antibiotic currently in development for the treatment of Clostridium difficileinfection. The comparative activities of SMT19969 and vancomycin against nonepidemic and epidemic strains of C. difficilewere studied in an established hamster model. Against nonepidemic (VA11) strains, the survival rates of SMT19969-treated animals ranged from 80% to 95%. Vancomycin exhibited 100% protection during treatment, with relapse observed starting on day 9 and 50% survival at day 20. At 50 mg/kg of body weight, SMT19969 administered orally once daily for 5 days provided full protection of treated animals on the dosing days and through day 12 against epidemic strains. Vancomycin also protected during the dosing interval, but apparent relapse occurred earlier, starting on day 11. SMT19969 exhibited excellent in vitroactivity, with MICs of 0.25 μg/ml for all isolates. The MICs for vancomycin were 2- to 4-fold higher at ≤0.5 to 1 μg/ml. All plasma sample concentrations of SMT19969 were below the limit of quantification (25 ng/ml) at all time points, consistent with the reported lack of bioavailability of the compound. Cecal concentrations were significantly above the MIC (ranging from 96 μg/ml to 172 μg/ml).

Published
2014
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46. Perturbation of Staphylococcus aureusGene Expression by the Enoyl-Acyl Carrier Protein Reductase Inhibitor AFN-1252

Author

Parsons, Joshua B., Kukula, Maciej, Jackson, Pamela, Pulse, Mark, Simecka, Jerry W., Valtierra, David, Weiss, William J., Kaplan, Nachum, and Rock, Charles O.

Abstract

ABSTRACTThis study examines the alteration in Staphylococcus aureusgene expression following treatment with the type 2 fatty acid synthesis inhibitor AFN-1252. An Affymetrix array study showed that AFN-1252 rapidly increased the expression of fatty acid synthetic genes and repressed the expression of virulence genes controlled by the SaeRS 2-component regulator in exponentially growing cells. AFN-1252 did not alter virulence mRNA levels in a saeRdeletion strain or in strain Newman expressing a constitutively active SaeS kinase. AFN-1252 caused a more pronounced increase in fabHmRNA levels in cells entering stationary phase, whereas the depression of virulence factor transcription was attenuated. The effect of AFN-1252 on gene expression in vivowas determined using a mouse subcutaneous granuloma infection model. AFN-1252 was therapeutically effective, and the exposure (area under the concentration-time curve from 0 to 48 h [AUC0–48]) of AFN-1252 in the pouch fluid was comparable to the plasma levels in orally dosed animals. The inhibition of fatty acid biosynthesis by AFN-1252 in the infected pouches was signified by the substantial and sustained increase in fabHmRNA levels in pouch-associated bacteria, whereas depression of virulence factor mRNA levels in the AFN-1252-treated pouch bacteria was not as evident as it was in exponentially growing cells in vitro. The trends in fabHand virulence factor gene expression in the animal were similar to those in slower-growing bacteria in vitro. These data indicate that the effects of AFN-1252 on virulence factor gene expression depend on the physiological state of the bacteria.

Published
2013
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47. Evaluation of Ceftazidime and NXL104 in Two Murine Models of Infection Due to KPC-Producing Klebsiella pneumoniae

Author

Endimiani, Andrea, Hujer, Kristine M., Hujer, Andrea M., Pulse, Mark E., Weiss, William J., and Bonomo, Robert A.

Abstract

ABSTRACTWe evaluated the efficacy of NXL104, a novel β-lactamase inhibitor, in combination with ceftazidime (CAZ) in two murine infection models (septicemia and thigh infection). We chose two KPC-producing Klebsiella pneumoniaestrains (VA-361 and VA-406) showing MICs of CAZ of ≥256 μg/ml. Septicemia was induced by the intraperitoneal injection of KPC-producing K. pneumoniaefollowed 30 min later by a single subcutaneous treatment with CAZ alone or CAZ-NXL104 in ratios of 2:1, 4:1, 8:1, and 16:1. In this model, the median effective doses for 50% (ED50) of the animals for CAZ alone versus VA-361 and VA-406 were 1,578 and 709 mg/kg of body weight, respectively. When combined with NXL104 at 2:1, 4:1, 8:1, and 16:1 ratios, the CAZ ED50s for VA-361 and VA-406 were reduced to 8.1 and 3.5 mg/kg, 15.1 and 3.8 mg/kg, 16.9 and 7.2 mg/kg, and 29.5 and 12.1 mg/kg, respectively. For thigh infection, neutropenia was induced by the intraperitoneal injection of cyclophosphamide at days −4 and −1 preinfection. Infection was established by the intramuscular injection of KPC-producing K. pneumoniaeinto the right thigh. Mice were treated 1.5 h postinfection with either CAZ alone or CAZ-NXL104 at constant ratios of 4:1. When thighs were removed at 24 h postinfection, a >2-log CFU reduction was observed for mice treated with CAZ-NXL104 at doses of ≥128:32 mg/kg. In contrast, CAZ doses of ≥1,024 mg/kg were unable to reduce the numbers of CFU. Despite resistance to CAZ and possessing a complex β-lactamase background, NXL104 combined with CAZ proved to be very effective in murine models of infection due to contemporary highly resistant KPC-producing K. pneumoniaeisolates.

Published
2010
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48. Microbiological Characterization of VNRX-5236, a Broad-Spectrum β-Lactamase Inhibitor for Rescue of the Orally Bioavailable Cephalosporin Ceftibuten as a Carbapenem-Sparing Agent against Strains of EnterobacteralesExpressing Extended-Spectrum β-Lactamases and Serine Carbapenemases

Author

Chatwin, Cassandra L., Hamrick, Jodie C., Trout, Robert E. L., Myers, Cullen L., Cusick, Susan M., Weiss, William J., Pulse, Mark E., Xerri, Luigi, Burns, Christopher J., Moeck, Gregory, Daigle, Denis M., John, Kaitlyn, Uehara, Tsuyoshi, and Pevear, Daniel C.

Abstract

There is an urgent need for oral agents to combat resistant Gram-negative pathogens. Here, we describe the characterization of VNRX-5236, a broad-spectrum boronic acid β-lactamase inhibitor (BLI), and its orally bioavailable etzadroxil prodrug, VNRX-7145.

Published
2021
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49. DAV131A Protects Hamsters from Lethal Clostridioides difficileInfection Induced by Fluoroquinolones

Author

Saint-Lu, Nathalie, Burdet, Charles, Sablier-Gallis, Frédérique, Corbel, Tanguy, Nevière, Agathe, Sayah-Jeanne, Sakina, Pulse, Mark, Weiss, William, Ferreira, Stéphanie, Andremont, Antoine, Mentré, France, and de Gunzburg, Jean

Abstract

Fluoroquinolone treatments induce dysbiosis of the intestinal microbiota, resulting in loss of resistance to colonization by exogenous bacteria such as Clostridioides difficilethat may cause severe diarrhea in humans and lethal infection in hamsters. We show here that DAV131A, a charcoal-based adsorbent, decreases the intestinal levels of the fluoroquinolone antibiotics levofloxacin and ciprofloxacin in hamsters, protects their intestinal microbiota, and prevents lethal infection by C. difficile.

Published
2019
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50. Activity of Meropenem-Vaborbactam against Carbapenem-Resistant Enterobacteriaceaein a Murine Model of Pyelonephritis

Author

Weiss, William J., Pulse, Mark E., Nguyen, Phung, Peterson, Kelly, Silva, Jessica, Simecka, Jerry W., Valtierra, David, Sabet, Mojgan, and Griffith, David C.

Abstract

ABSTRACTThe recently approved combination of meropenem and vaborbactam (Vabomere) is highly active against Gram-negative pathogens, especially Klebsiella pneumoniaecarbapenemase (KPC)-producing, carbapenem-resistant Enterobacteriaceae. We evaluated the efficacy of meropenem-vaborbactam against three clinically relevant isolates in a murine pyelonephritis model. The data indicate that the combination of meropenem and vaborbactam significantly increased bacterial killing compared to that with the untreated controls. These data suggest that this combination may have utility in the treatment of complicated urinary tract infections due to KPC-producing, carbapenem-resistant Enterobacteriaceae.

Published
2017
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