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Bonomo Robert

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https://www.readbyqxmd.com/read/29144725/inhibition-of-acinetobacter-derived-cephalosporinase-adc-exploring-the-carboxylate-recognition-site-using-novel-%C3%AE-lactamase-inhibitors
#1
Emilia Caselli, Chiara Romagnoli, Rachel A Powers, Magdalena A Taracila, Alexandra A Bouza, Hollister C Swanson, Kali A Smolen, Francesco Fini, Bradley J Wallar, Robert A Bonomo, Fabio Prati
Boronic acids are attracting a lot of attention as -lactamase inhibitors, and in particular compound S02030 (Ki = 44 nM) proved to be a good lead compound against ADC-7 (Acinetobacter Derived Cephalosporinase), one of the most significant resistance determinants in A. baumannii. The atomic structure of the ADC-7/S02030 complex highlighted the importance of critical structural determinants for recognition of the boronic acids. Herein, to elucidate the role in recognition of the R2-carboxylate, which mimics the C3/C4 found in -lactams, we designed, synthesized, and characterized six derivatives of S02030 (3a)...
November 16, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/29144724/structure-based-analysis-of-boronic-acids-as-inhibitors-of-acinetobacter-derived-cephalosporinase-7-adc-7-a-unique-class-c-%C3%AE-lactamase
#2
Alexandra A Bouza, Hollister C Swanson, Kali A Smolen, Alison L VanDine, Magdalena A Taracila, Chiara Romagnoli, Emilia Caselli, Fabio Prati, Robert A Bonomo, Rachel A Powers, Bradley J Wallar
Acinetobacter baumannii is a multidrug resistant pathogen that infects more than 12,000 patients each year in the US. Much of the resistance to β-lactam antibiotics in Acinetobacter spp. is a result of class C β-lactamases known as Acinetobacter-derived cephalosporinases (ADCs). ADCs are unaffected by clinically used -lactam-based β-lactamase inhibitors. In this study, five boronic acid transition state analog inhibitors (BATSIs) were evaluated for inhibition of the class C cephalosporinase ADC-7. Our goal was to explore the properties of BATSIs designed to probe the R1 binding site...
November 16, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/29133567/risk-factors-and-outcomes-associated-with-multidrug-resistant-acinetobacter-baumannii-upon-icu-admission
#3
Natalia Blanco, Anthony D Harris, Clare Rock, J Kristie Johnson, Lisa Pineles, Robert A Bonomo, Arjun Srinivasan, Melinda M Pettigrew, Kerri A Thom
Introduction: Multi-drug resistant (MDR) Acinetobacter baumannii, associated with broad-spectrum antibiotic use, is an important nosocomial pathogen associated with morbidity and mortality. This study aimed to investigate the prevalence of MDR A. baumannii perirectal colonization among adult patients at ICU admission over a 5-year period, and to identify risk factors and outcomes associated with colonization.Methods: A retrospective cohort analysis of patients admitted to the medical (MICU) and surgical intensive care units (SICU) at the University of Maryland Medical Center from May 2005 to September 2009 was performed using perirectal surveillance cultures on admission...
November 13, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29117557/the-role-of-eif6-in-skeletal-muscle-homeostasis-revealed-by-endurance-training-co-expression-networks
#4
Kim Clarke, Sara Ricciardi, Tim Pearson, Izwan Bharudin, Peter K Davidsen, Michela Bonomo, Daniela Brina, Alessandra Scagliola, Deborah M Simpson, Robert J Beynon, Farhat Khanim, John Ankers, Mark A Sarzynski, Sujoy Ghosh, Addolorata Pisconti, Jan Rozman, Martin Hrabe de Angelis, Chris Bunce, Claire Stewart, Stuart Egginton, Mark Caddick, Malcolm Jackson, Claude Bouchard, Stefano Biffo, Francesco Falciani
Regular endurance training improves muscle oxidative capacity and reduces the risk of age-related disorders. Understanding the molecular networks underlying this phenomenon is crucial. Here, by exploiting the power of computational modeling, we show that endurance training induces profound changes in gene regulatory networks linking signaling and selective control of translation to energy metabolism and tissue remodeling. We discovered that knockdown of the mTOR-independent factor Eif6, which we predicted to be a key regulator of this process, affects mitochondrial respiration efficiency, ROS production, and exercise performance...
November 7, 2017: Cell Reports
https://www.readbyqxmd.com/read/29091730/probing-the-interaction-of-aspergillomarasmine-a-with-metallo-%C3%AE-lactamases-ndm-1-vim-2-and-imp-7
#5
Alexander Bergstrom, Andrew Katko, Zach Adkins, Jessica Hill, Zishuo Cheng, Mia Burnett, Hao Yang, Mahesh Aitha, M Rachel Mehaffey, Jennifer S Brodbelt, Kamaleddin H M E Tehrani, Nathaniel I Martin, Robert A Bonomo, Richard C Page, David L Tierney, Walter Fast, Gerard D Wright, Michael W Crowder
Metallo-β-lactamases (MBLs) are a growing threat to the continued efficacy of β-lactam antibiotics. Recently, aspergillomarasmine A (AMA) was identified as an MBL inhibitor, but the mode of inhibition was not fully characterized. Equilibrium dialysis and metal analysis studies revealed that 2 equiv of AMA effectively removes 1 equiv of Zn(II) from MBLs NDM-1, VIM-2, and IMP-7 when the MBL is at micromolar concentrations. Conversely, (1)H NMR studies revealed that 2 equiv of AMA remove 2 equiv of Co(II) from Co(II)-substituted NDM-1, VIM-2, and IMP-7 when the MBL/AMA are at millimolar concentrations...
November 9, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/29089425/klebsiella-pneumoniae-carbapenemase-2-kpc-2-substitutions-at-ambler-position-asp179-and-resistance-to-ceftazidime-avibactam-unique-antibiotic-resistant-phenotypes-emerge-from-%C3%AE-lactamase-protein-engineering
#6
Melissa D Barnes, Marisa L Winkler, Magdalena A Taracila, Malcolm G Page, Eric Desarbre, Barry N Kreiswirth, Ryan K Shields, Minh-Hong Nguyen, Cornelius Clancy, Brad Spellberg, Krisztina M Papp-Wallace, Robert A Bonomo
The emergence of Klebsiella pneumoniae carbapenemases (KPCs), β-lactamases that inactivate "last-line" antibiotics such as imipenem, represents a major challenge to contemporary antibiotic therapies. The combination of ceftazidime (CAZ) and avibactam (AVI), a potent β-lactamase inhibitor, represents an attempt to overcome this formidable threat and to restore the efficacy of the antibiotic against Gram-negative bacteria bearing KPCs. CAZ-AVI-resistant clinical strains expressing KPC variants with substitutions in the Ω-loop are emerging...
October 31, 2017: MBio
https://www.readbyqxmd.com/read/29079150/influence-of-aging-and-environment-on-presentation-of-infection-in-older-adults
#7
REVIEW
Nadim G El Chakhtoura, Robert A Bonomo, Robin L P Jump
In older adults, pathophysiologic, clinical, and environmental factors all affect the presentation of infections. We explore how age-related changes influence the manifestation and evaluation of infections in this population. Specific topics include immunosenescence, age-related organ-specific physiologic changes, and frailty. We also describe clinical factors influencing infection risk and presentation in older adults, including temperature regulation, cognitive decline, and malnutrition. Finally, we discuss the influence of the setting in which older adults reside on the clinical evaluation of infection...
December 2017: Infectious Disease Clinics of North America
https://www.readbyqxmd.com/read/29064133/-double-carbapenem-and-oral-fosfomycin-for-the-treatment-of-complicated-urinary-tract-infections-caused-by-blandm-harboring-enterobacteriaceae-in-kidney-transplantation
#8
Rossana Rosa, Susan D Rudin, Laura J Rojas, Andrea M Hujer, Armando Perez-Cardona, Federico Perez, Robert A Bonomo, Octavio Martinez, Lilian M Abbo, Jose F Camargo
Infections with carbapenemase-producing carbapenem-resistant Enterobacteriaceae represent an emergent problem worldwide. Treatment of infections caused by New Delhi metallo-beta-lactamase (NDM)-harboring Enterobacteriaceae is particularly challenging as it frequently involves the use of nephrotoxic agents, which is problematic in kidney transplant recipients and non-renal transplants with marginal kidney function. We present two cases of urinary tract infections caused by NDM-harboring Enterobacteriaceae successfully treated with a combination of "double carbapenem" and oral fosfomycin...
October 24, 2017: Transplant Infectious Disease: An Official Journal of the Transplantation Society
https://www.readbyqxmd.com/read/29038264/clinical-evolution-of-new-delhi-metallo-%C3%AE-lactamase-ndm-optimizes-resistance-under-zn-ii-deprivation
#9
Guillermo Bahr, Luisina Vitor-Horen, Christopher R Bethel, Robert A Bonomo, Lisandro J González, Alejandro J Vila
Carbapenem-resistant Enterobacteriaceae (CRE) are rapidly spreading and taking a staggering toll on all healthcare systems, largely due to the dissemination of genes coding for potent carbapenemases. An important family of carbapenemases are the Zn(II)-dependent β-lactamases, known as Metallo-β-lactamases (MBLs). Among them, the New-Delhi Metallo-β-lactamase (NDM) has experienced the fastest and widest geographical spread. While other clinically important MBLs are soluble periplasmic enzymes, NDM β-lactamases are lipoproteins anchored to the outer membrane in Gram-negative bacteria...
October 16, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29029188/an-analysis-of-the-epidemic-of-kpc-producing-klebsiella-pneumoniae-convergence-of-two-evolutionary-mechanisms-creates-the-perfect-storm
#10
Laura J Rojas, George M Weinstock, Elsa De La Cadena, Lorena Diaz, Rafael Rios, Blake M Hanson, Joseph S Brown, Purva Vats, Daniel S Phillips, Hoan Nguyen, Kristine M Hujer, Adriana Correa, Mark D Adams, Federico Perez, Erica Sodergren, Apurva Narechania, Paul J Planet, Maria V Villegas, Robert A Bonomo, Cesar A Arias
Background: Carbapenem resistance is a critical health care challenge worldwide. Particularly concerning is the widespread dissemination of Klebsiella pneumoniae carbapenemase (KPC). K. pneumoniae harboring blaKPC (KPC-Kpn) is endemic in many areas including United States, where the epidemic was primarily mediated by the clonal dissemination of Kpn ST258. We postulated that the spread of blaKPC in other regions occurs by different and more complex mechanisms. To test this, we investigated the evolution and dynamics of spread of KPC-Kpn in Colombia, where KPC became rapidly endemic after emerging in 2005...
September 27, 2017: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/29026866/a-prospective-observational-study-of-the-epidemiology-management-and-outcomes-of-skin-and-soft-tissue-infections-due-to-carbapenem-resistant-enterobacteriaceae
#11
Oryan Henig, Eric Cober, Sandra S Richter, Federico Perez, Robert A Salata, Robert C Kalayjian, Richard R Watkins, Steve Marshall, Susan D Rudin, T Nicholas Domitrovic, Andrea M Hujer, Kristine M Hujer, Yohei Doi, Scott Evans, Vance G Fowler, Robert A Bonomo, David van Duin, Keith S Kaye
BACKGROUND: This study was performed to characterize the epidemiology, management, and outcomes of skin and soft tissue infection (SSTI) and colonization due to carbapenem-resistant Enterobacteriaceae (CRE). METHODS: Patients from the Consortium on Resistance Against Carbapenem in Klebsiella and Other Enterobacteriaceae (CRACKLE-1) from December 24, 2011 to October 1, 2014 with wound cultures positive for CRE were included in the study. Predictors of surgical intervention were analyzed...
2017: Open Forum Infectious Diseases
https://www.readbyqxmd.com/read/29020404/colistin-vs-ceftazidime-avibactam-in-the-treatment-of-infections-due-to-carbapenem-resistant-enterobacteriaceae
#12
David van Duin, Judith J Lok, Michelle Earley, Eric Cober, Sandra S Richter, Federico Perez, Robert A Salata, Robert C Kalayjian, Richard R Watkins, Yohei Doi, Keith S Kaye, Vance G Fowler, David L Paterson, Robert A Bonomo, Scott Evans
Background: The efficacy of ceftazidime-avibactam - a cephalosporin-β-lactamase inhibitor combination with in vitro activity against Klebsiella pneumoniae carbapenemase (KPC)-producing carbapenem-resistant Enterobacteriaceae (CRE) - as compared to colistin remains unknown. Methods: Patients initially treated with either ceftazidime-avibactam or colistin for CRE infections were selected from the Consortium on resistance against carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE), a prospective, multicenter, observational study...
September 4, 2017: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
https://www.readbyqxmd.com/read/29020250/empiric-therapy-with-carbapenem-sparing-regimens-for-bloodstream-infections-due-to-extended-spectrum-%C3%AE-lactamase-producing-enterobacteriaceae-results-from-the-increment-cohort
#13
Zaira Raquel Palacios-Baena, Belén Gutiérrez-Gutiérrez, Esther Calbo, Benito Almirante, Pierluigi Viale, Antonio Oliver, Vicente Pintado, Oriol Gasch, Luis Martínez-Martínez, Johann Pitout, Murat Akova, Carmen Peña, José Molina Gil-Bermejo, Alicia Hernández, Mario Venditti, Nuria Prim, German Bou, Evelina Tacconelli, Mario Tumbarello, Axel Hamprecht, Helen Giamarellou, Manel Almela, Federico Pérez, Mitchell J Schwaber, Joaquín Bermejo, Warren Lowman, Po-Ren Hsueh, José Ramón Paño-Pardo, Julián Torre-Cisneros, Maria Souli, Robert A Bonomo, Yehuda Carmeli, David L Paterson, Álvaro Pascual, Jesús Rodríguez-Baño
Background: There is little information about the efficacy of active alternative drugs to carbapenems except β-lactam/β-lactamase inhibitors for the treatment of bloodstream infections (BSIs) due to extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-E). The objective of this study was to assess the outcomes of patients with BSI due to ESBL-E who received empiric therapy with such drugs (other active drugs [OADs]) or carbapenems. Methods: A multinational retrospective cohort study of patients with BSI due to ESBL-E who received empiric treatment with OADs or carbapenems was performed...
October 30, 2017: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
https://www.readbyqxmd.com/read/29017266/reply-to-macesic-et-al
#14
David van Duin, Robert A Bonomo
No abstract text is available yet for this article.
August 15, 2017: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
https://www.readbyqxmd.com/read/29017264/application-of-precision-medicine-through-the-molecular-characterization-of-extensively-drug-resistant-klebsiella-pneumoniae-in-a-multivisceral-transplant-patient
#15
Rossana Rosa, Susan D Rudin, Laura J Rojas, Armando Perez-Cardona, Laura Aragon, David P Nicolau, Federico Perez, Andrea M Hujer, Akin Tekin, Octavio Martinez, Jose F Camargo, Robert A Bonomo, Lilian M Abbo
No abstract text is available yet for this article.
August 15, 2017: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
https://www.readbyqxmd.com/read/29017247/a-17-year-nationwide-study-of-burkholderia-cepacia-complex-bloodstream-infections-among-patients-in-the-united-states-veterans-health-administration
#16
Nadim G El Chakhtoura, Elie Saade, Brigid M Wilson, Federico Perez, Krisztina M Papp-Wallace, Robert A Bonomo
Background: Burkholderia cepacia complex (Bcc) are a group of multidrug-resistant gram-negative bacteria rarely reported in patients without cystic fibrosis (CF) or immunocompromising conditions. We investigated Bcc bloodstream infections (BSIs) in a cohort of non-CF patients from the US Veterans Health Administration (VHA). Methods: Using VHA databases, we identified patients with Bcc BSI at facilities nationwide from 1999 through 2015. We ascertained clinical characteristics, treatments, and outcomes and identified factors associated with 30-day mortality in logistic regression analysis...
October 15, 2017: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
https://www.readbyqxmd.com/read/28965402/clinical-variants-of-new-delhi-metallo-%C3%AE-lactamase-are-evolving-to-overcome-zinc-scarcity
#17
Alesha C Stewart, Christopher R Bethel, Jamie VanPelt, Alex Bergstrom, Zishuo Cheng, Callie G Miller, Cameron Williams, Robert Poth, Matthew Morris, Olivia Lahey, Jay C Nix, David L Tierney, Richard C Page, Michael W Crowder, Robert A Bonomo, Walter Fast
Use and misuse of antibiotics have driven the evolution of serine β-lactamases to better recognize new generations of β-lactam drugs, but the selective pressures driving evolution of metallo-β-lactamases are less clear. Here, we present evidence that New Delhi metallo-β-lactamase (NDM) is evolving to overcome the selective pressure of zinc(II) scarcity. Studies of NDM-1, NDM-4 (M154L), and NDM-12 (M154L, G222D) demonstrate that the point mutant M154L, contained in 50% of clinical NDM variants, selectively enhances resistance to the penam ampicillin at low zinc(II) concentrations relevant to infection sites...
October 11, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28948921/combination-therapy-for-bloodstream-infections-with-carbapenemase-producing-enterobacteriaceae-authors-reply
#18
Belén Gutiérrez-Gutiérrez, Robert A Bonomo, Yehuda Carmeli, David L Paterson, Alvaro Pascual, Jesús Rodríguez-Baño
No abstract text is available yet for this article.
October 2017: Lancet Infectious Diseases
https://www.readbyqxmd.com/read/28931235/monoclonal-antibody-protects-against-acinetobacter-baumannii-infection-by-enhancing-bacterial-clearance-and-evading-sepsis
#19
Travis B Nielsen, Paul Pantapalangkoor, Brian M Luna, Kevin W Bruhn, Jun Yan, Ken Dekitani, Sarah Hsieh, Brandon Yeshoua, Bryan Pascual, Evgeny Vinogradov, Kristine M Hujer, T Nicholas Domitrovic, Robert A Bonomo, Thomas A Russo, Magda Lesczcyniecka, Thomas Schneider, Brad Spellberg
Background: Extremely drug-resistant (XDR) Acinetobacter baumannii is one of the most commonly encountered, highly resistant pathogens requiring novel therapeutic interventions. Methods: We developed C8, a monoclonal antibody (mAb), by immunizing mice with sublethal inocula of a hypervirulent XDR clinical isolate. Results: C8 targets capsular carbohydrate on the bacterial surface, enhancing opsonophagocytosis. Treating with a single dose of C8 as low as 0...
August 15, 2017: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/28912448/a-general-reaction-mechanism-for-carbapenem-hydrolysis-by-mononuclear-and-binuclear-metallo-%C3%AE-lactamases
#20
María-Natalia Lisa, Antonela R Palacios, Mahesh Aitha, Mariano M González, Diego M Moreno, Michael W Crowder, Robert A Bonomo, James Spencer, David L Tierney, Leticia I Llarrull, Alejandro J Vila
Carbapenem-resistant Enterobacteriaceae threaten human health, since carbapenems are last resort drugs for infections by such organisms. Metallo-β-lactamases (MβLs) are the main mechanism of resistance against carbapenems. Clinically approved inhibitors of MBLs are currently unavailable as design has been limited by the incomplete knowledge of their mechanism. Here, we report a biochemical and biophysical study of carbapenem hydrolysis by the B1 enzymes NDM-1 and BcII in the bi-Zn(II) form, the mono-Zn(II) B2 Sfh-I and the mono-Zn(II) B3 GOB-18...
September 14, 2017: Nature Communications
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