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8. Discovery of Platencin, a Dual FabF and FabH Inhibitor with in vivo Antibiotic Properties

Author

Wang, Jun, Kodali, Srinivas, Lee, Sang Ho, Galgoci, Andrew, Painter, Ronald, Dorso, Karen, Racine, Fred, Motyl, Mary, Hernandez, Lorraine, Tinney, Elizabeth, Colletti, Steven L., Herath, Kithsiri, Cummings, Richard, Salazar, Oscar, González, Ignacio, Basilio, Angela, Vicente, Francisca, Genilloud, Olga, Pelaez, Fernando, Jayasuriya, Hiranthi, Young, Katherine, Cully, Doris F., and Singh, Sheo B.

Published
2007
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9. Ibrexafungerp: An orally active β-1,3-glucan synthesis inhibitor

Author

Apgar, James M., Wilkening, Robert R., Parker, Dann L., Jr., Meng, Dongfang, Wildonger, Kenneth J., Sperbeck, Donald, Greenlee, Mark L., Balkovec, James M., Flattery, Amy M., Abruzzo, George K., Galgoci, Andrew M., Giacobbe, Robert A., Gill, Charles J., Hsu, Ming-Jo, Liberator, Paul, Misura, Andrew S., Motyl, Mary, Nielsen Kahn, Jennifer, Powles, Maryann, Racine, Fred, Dragovic, Jasminka, Fan, Weiming, Kirwan, Robin, Lee, Shu, Liu, Hao, Mamai, Ahmed, Nelson, Kingsley, and Peel, Michael

Published
2021
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10. MK-5204: An orally active β-1,3-glucan synthesis inhibitor

Author

Apgar, James M., Wilkening, Robert R., Parker, Dann L., Jr., Meng, Dongfang, Wildonger, Kenneth J., Sperbeck, Donald, Greenlee, Mark L., Balkovec, James M., Flattery, Amy M., Abruzzo, George K., Galgoci, Andrew M., Giacobbe, Robert A., Gill, Charles J., Hsu, Ming-Jo, Liberator, Paul, Misura, Andrew S., Motyl, Mary, Kahn, Jennifer Nielsen, Powles, Maryann, Racine, Fred, Dragovic, Jasminka, Fan, Weiming, Kirwan, Robin, Lee, Shu, Liu, Hao, Mamai, Ahmed, Nelson, Kingsley, and Peel, Michael

Published
2020
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11. In Vitro Hollow-Fiber Studies Assessing Antibacterial Activity of Ceftolozane/Tazobactam Against Multidrug-Resistant Pseudomonas Aeruginosa

Author

Carr, Donna, primary, Zhang, Zufei, additional, Si, Qian, additional, Racine, Fred, additional, Xiao, Jing Chen, additional, Katwaru, Ravi, additional, Wismer, Michael K, additional, Johnson, Matthew G, additional, Feng, Hwa-Ping, additional, Young, Katherine, additional, Rizk, Matthew L, additional, and Motyl, Mary, additional

Published
2020
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13. Additional file 3: of In vitro studies evaluating the activity of imipenem in combination with relebactam against Pseudomonas aeruginosa

Author

Young, Katherine, Painter, Ronald, Raghoobar, Susan, Hairston, Nichelle, Racine, Fred, Wisniewski, Douglas, Balibar, Carl, Artjohn Villafania, Rumin Zhang, Sahm, Daniel, Blizzard, Timothy, Murgolo, Nicholas, Hammond, Milton, and Motyl, Mary

Abstract

Table S1. P aeruginosa isolate sources. Table S2. Primers used in the construction of P. aeruginosa RND-overexpressing strains. Table S3. Inoculum effect control data. Table S4. Susceptibility to imipenem and the combination of imipenem with relebactam 4â Îźg/mL by PDC allele. (DOCX 25 kb)

Published
2019
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15. Additional file 2: of In vitro studies evaluating the activity of imipenem in combination with relebactam against Pseudomonas aeruginosa

Author

Young, Katherine, Painter, Ronald, Raghoobar, Susan, Hairston, Nichelle, Racine, Fred, Wisniewski, Douglas, Balibar, Carl, Artjohn Villafania, Rumin Zhang, Sahm, Daniel, Blizzard, Timothy, Murgolo, Nicholas, Hammond, Milton, and Motyl, Mary

Abstract

Figure S1. Mechanistic profiling by global progress curve analysis. (DOCX 81 kb)

Published
2019
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16. Additional file 4: of In vitro studies evaluating the activity of imipenem in combination with relebactam against Pseudomonas aeruginosa

Author

Young, Katherine, Painter, Ronald, Raghoobar, Susan, Hairston, Nichelle, Racine, Fred, Wisniewski, Douglas, Balibar, Carl, Artjohn Villafania, Rumin Zhang, Sahm, Daniel, Blizzard, Timothy, Murgolo, Nicholas, Hammond, Milton, and Motyl, Mary

Abstract

Figure S1. Minimum inhibitory concentrations (MIC50/90, expressed in Îźg/mL) for imipenem (A) and imipenem with 4â Îźg/mL relebactam (B), mapped onto a dendrogram of P. aeruginosa PDC alleles. (PDF 1384 kb)

Published
2019
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17. Exploring the Pharmacokinetic/Pharmacodynamic Relationship of Relebactam (MK-7655) in Combination with Imipenem in a Hollow-Fiber Infection Model

Author

Wu, Jin, primary, Racine, Fred, additional, Wismer, Michael K., additional, Young, Katherine, additional, Carr, Donna M., additional, Xiao, Jing C., additional, Katwaru, Ravi, additional, Si, Qian, additional, Harradine, Paul, additional, Motyl, Mary, additional, Bhagunde, Pratik R., additional, and Rizk, Matthew L., additional

Published
2018
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18. Novel orally active inhibitors of β-1,3-glucan synthesis derived from enfumafungin

Author

Apgar, James M., Wilkening, Robert R., Greenlee, Mark L., Balkovec, James M., Flattery, Amy M., Abruzzo, George K., Galgoci, Andrew M., Giacobbe, Robert A., Gill, Charles J., Hsu, Ming Jo, Liberator, Paul, Misura, Andrew S., Motyl, Mary, Nielsen Kahn, Jennifer, Powles, Maryann, Racine, Fred, Dragovic, Jasminka, Habulihaz, Bahanu, Fan, Weiming, Kirwan, Robin, Lee, Shu, Liu, Hao, Mamai, Ahmed, Nelson, Kingsley, and Peel, Michael

Published
2015
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22. Discovery of platencin, a dual FabF and FabH inhibitor with in vivo antibiotic properties.

Author

Jun Wang, Kodali, Srinivas, Sang Ho Lee, Galgoci, Andrew, Painter, Ronald, Dorso, Karen, Racine, Fred, Motyl, Mary, Hernandez, Lorraine, Tinney, Elizabeth, Colletti, Steven L., Herath, Kithsiri, Cummings, Richard, Salazar, Oscar, González, Lgnacio, Basilio, Angela, Vicente, Francisca, Genilioud, Olga, Peiaez, Fernando, and Jayasuriya, Hiranthi

Subjects
ANTIBIOTICS, ANTIBACTERIAL agents, ANTI-infective agents, VANCOMYCIN, ENTEROCOCCUS, STAPHYLOCOCCUS aureus
Abstract

Emergence of bacterial resistance is a major issue for all classes of antibiotics; therefore, the identification of new classes is critically needed. Recently we reported the discovery of platensimycin by screening natural product extracts using a target-based whole-cell strategy with antisense silencing technology in concert with cell free biochemical validations. Continued screening efforts led to the discovery of platencin, a novel natural product that is chemically and biologically related but different from platensimycin. Platencin exhibits a broad-spectrum Gram-positive antibacterial activity through inhibition of fatty acid biosynthesis. It does not exhibit cross-resistance to key antibiotic resistant strains tested, including methicillin-resistant Staphylococcus aureus, vancomycin-intermediate S. aureus, and vancomycin-resistant Enterococci. Platencin shows potent in vivo efficacy without any observed toxicity. It targets two essential proteins, β-ketoacyl-[acyl carrier protein (ACP)] synthase II (FabF) and III (FabH) with IC50 values of 1.95 and 3.91 μg/ml, respectively, whereas platensimycin targets only FabF (IC50 = 0.13 μg/ml) in S. aureus, emphasizing the fact that more antibiotics with novel structures and new modes of action can be discovered by using this antisense differential sensitivity whole-cell screening paradigm. [ABSTRACT FROM AUTHOR]

Published
2007
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23. Broad Coverage of Genetically Diverse Strains of Clostridium difficileby Actoxumab and Bezlotoxumab Predicted by In VitroNeutralization and Epitope Modeling

Author

Hernandez, Lorraine D., Racine, Fred, Xiao, Li, DiNunzio, Edward, Hairston, Nichelle, Sheth, Payal R., Murgolo, Nicholas J., and Therien, Alex G.

Abstract

ABSTRACTClostridium difficileinfections (CDIs) are the leading cause of hospital-acquired infectious diarrhea and primarily involve two exotoxins, TcdA and TcdB. Actoxumab and bezlotoxumab are human monoclonal antibodies that neutralize the cytotoxic/cytopathic effects of TcdA and TcdB, respectively. In a phase II clinical study, the actoxumab-bezlotoxumab combination reduced the rate of CDI recurrence in patients who were also treated with standard-of-care antibiotics. However, it is not known whether the antibody combination will be effective against a broad range of C. difficilestrains. As a first step toward addressing this, we tested the ability of actoxumab and bezlotoxumab to neutralize the activities of toxins from a number of clinically relevant and geographically diverse strains of C. difficile. Neutralization potencies, as measured in a cell growth/survival assay with purified toxins from various C. difficilestrains, correlated well with antibody/toxin binding affinities. Actoxumab and bezlotoxumab neutralized toxins from culture supernatants of all clinical isolates tested, including multiple isolates of the BI/NAP1/027 and BK/NAP7/078 strains, at antibody concentrations well below plasma levels observed in humans. We compared the bezlotoxumab epitopes in the TcdB receptor binding domain across known TcdB sequences and found that key substitutions within the bezlotoxumab epitopes correlated with the relative differences in potencies of bezlotoxumab against TcdB of some strains, including ribotypes 027 and 078. Combined with in vitroneutralization data, epitope modeling will enhance our ability to predict the coverage of new and emerging strains by actoxumab-bezlotoxumab in the clinic.

Published
2014
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24. Caspofungin Susceptibility in Aspergillusand Non-AspergillusMolds: Inhibition of Glucan Synthase and Reduction of β-d-1,3 Glucan Levels in Culture

Author

Kahn, Jennifer Nielsen, Hsu, Ming-Jo, Racine, Fred, Giacobbe, Robert, and Motyl, Mary

Abstract

ABSTRACTCaspofungin inhibits synthesis of β-d-1,3 glucan, essential to cell walls in Candidaand Aspergillusspp., but activity against less common molds is largely uncharacterized. We demonstrate that caspofungin inhibits β-d-1,3 glucan synthesis and reduces in vitro growth of clinical isolates from the genera Alternaria, Curvularia, Scedosporium, Acremonium, Bipolaris, and Trichoderma.

Published
2006
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25. Caspofungin susceptibility in Aspergillus and non-Aspergillus molds: inhibition of glucan synthase and reduction of beta-D-1,3 glucan levels in culture.

Author

Kahn JN, Hsu MJ, Racine F, Giacobbe R, and Motyl M

Subjects
Aspergillus fumigatus genetics, Aspergillus fumigatus growth & development, Aspergillus fumigatus isolation & purification, Caspofungin, Echinocandins, Fluorescent Dyes, Fungi genetics, Fungi growth & development, Fungi isolation & purification, In Vitro Techniques, Lipopeptides, Microbial Sensitivity Tests, Antifungal Agents pharmacology, Aspergillus fumigatus drug effects, Fungi drug effects, Glucosyltransferases antagonists & inhibitors, Peptides, Cyclic pharmacology, beta-Glucans metabolism
Abstract

Caspofungin inhibits synthesis of beta-D-1,3 glucan, essential to cell walls in Candida and Aspergillus spp., but activity against less common molds is largely uncharacterized. We demonstrate that caspofungin inhibits beta-D-1,3 glucan synthesis and reduces in vitro growth of clinical isolates from the genera Alternaria, Curvularia, Scedosporium, Acremonium, Bipolaris, and Trichoderma.

Published
2006
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