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https://www.readbyqxmd.com/read/29680579/the-continuing-challenge-of-metallo-%C3%AE-lactamase-inhibition-mechanism-matters
#1
REVIEW
Lin-Cheng Ju, Zishuo Cheng, Walter Fast, Robert A Bonomo, Michael W Crowder
Metallo-β-lactamases (MBLs) are a significant clinical problem because they hydrolyze and inactivate nearly all β-lactam-containing antibiotics. These 'lifesaving drugs' constitute >50% of the available contemporary antibiotic arsenal. Despite the global spread of MBLs, MBL inhibitors have not yet appeared in clinical trials. Most MBL inhibitors target active site zinc ions and vary in mechanism from ternary complex formation to metal ion stripping. Importantly, differences in mechanism can impact pharmacology in terms of reversibility, target selectivity, and structure-activity relationship interpretation...
April 18, 2018: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/29675000/exploring-additional-dimensions-of-complexity-in-inhibitor-design-for-serine-%C3%AE-lactamases-mechanistic-and-intra-and-inter-molecular-chemistry-approaches
#2
REVIEW
Focco van den Akker, Robert A Bonomo
As a bacterial resistance strategy, serine β-lactamases have evolved from cell wall synthesizing enzymes known as penicillin-binding proteins (PBP), by not only covalently binding β-lactam antibiotics but, also acquiring mechanisms of deacylating these antibiotics. This critical deacylation step leads to release of hydrolyzed and inactivated β-lactams, thereby providing resistance for the bacteria against these antibiotics targeting the cell wall. To combat β-lactamase-mediated antibiotic resistance, numerous β-lactamase inhibitors were developed that utilize various strategies to inactivate the β-lactamase...
2018: Frontiers in Microbiology
https://www.readbyqxmd.com/read/29627985/strategic-approaches-to-overcome-resistance-against-gram-negative-pathogens-using-%C3%AE-lactamase-inhibitors-and-%C3%AE-lactam-enhancers-activity-of-three-novel-diazabicyclooctanes-wck-5153-zidebactam-wck-5107-and-wck-4234
#3
Krisztina M Papp-Wallace, Nhu Q Nguyen, Michael R Jacobs, Christopher R Bethel, Melissa D Barnes, Vijay Kumar, Saralee Bajaksouzian, Susan D Rudin, Philip N Rather, Satish Bhavsar, Tadiparthi Ravikumar, Prasad K Deshpande, Vijay Patil, Ravindra Yeole, Sachin S Bhagwat, Mahesh V Patel, Focco van den Akker, Robert A Bonomo
Limited treatment options exist to combat infections caused by multidrug-resistant (MDR) Gram-negative bacteria possessing broad-spectrum β-lactamases. The design of novel β-lactamase inhibitors is of paramount importance. Here, three novel diazabicyclooctanes (DBOs), WCK 5153, zidebactam (WCK 5107), and WCK 4234 (compounds 1-3, respectively), were synthesized and biochemically characterized against clinically important bacteria. Compound 3 inhibited class A, C, and D β-lactamases with unprecedented k2 / K values against OXA carbapenemases...
April 20, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29618394/comparison-of-predictors-and-mortality-between-bloodstream-infections-caused-by-esbl-producing-escherichia-coli-and-esbl-producing-klebsiella-pneumoniae
#4
Oded Scheuerman, Vered Schechner, Yehuda Carmeli, Belen Gutiérrez-Gutiérrez, Esther Calbo, Benito Almirante, Pier-Luigy Viale, Antonio Oliver, Patricia Ruiz-Garbajosa, Oriol Gasch, Monica Gozalo, Johann Pitout, Murat Akova, Carmen Peña, Jose Molina, Alicia Hernández-Torres, Mario Venditti, Nuria Prim, Julia Origüen, German Bou, Evelina Tacconelli, Maria Tumbarello, Axel Hamprecht, Ilias Karaiskos, Cristina de la Calle, Federico Pérez, Mitchell J Schwaber, Joaquin Bermejo, Warren Lowman, Po-Ren Hsueh, Carolina Navarro-San Francisco, Robert A Bonomo, David L Paterson, Alvaro Pascual, Jesus Rodríguez-Baño
OBJECTIVETo compare the epidemiology, clinical characteristics, and mortality of patients with bloodstream infections (BSI) caused by extended-spectrum β-lactamase (ESBL)-producing Escherichia coli (ESBL-EC) versus ESBL-producing Klebsiella pneumoniae (ESBL-KP) and to examine the differences in clinical characteristics and outcome between BSIs caused by isolates with CTX-M versus other ESBL genotypesMETHODSAs part of the INCREMENT project, 33 tertiary hospitals in 12 countries retrospectively collected data on adult patients diagnosed with ESBL-EC BSI or ESBL-KP BSI between 2004 and 2013...
April 5, 2018: Infection Control and Hospital Epidemiology
https://www.readbyqxmd.com/read/29610205/relebactam-is-a-potent-inhibitor-of-the-kpc-2-%C3%AE-lactamase-and-restores-the-susceptibility-of-imipenem-against-kpc-producing-enterobacteriaceae
#5
Krisztina M Papp-Wallace, Melissa D Barnes, Jim Alsop, Magdalena A Taracila, Christopher R Bethel, Scott A Becka, David van Duin, Barry N Kreiswirth, Keith S Kaye, Robert A Bonomo
The imipenem-relebactam combination is in development as a potential treatment regimen for infections caused by Enterobacteriaceae possessing complex β-lactamase backgrounds. Relebactam is a β-lactamase inhibitor that possesses the diazabicyclooctane core similar to avibactam, however relebactam's R1 side chain also includes a piperidine ring compared to the carboxyamide of avibactam. Here, we investigated the inactivation of Klebsiella pneumoniae carbapenemase (KPC-2), the most widespread class A carbapenemase, by relebactam and performed susceptibility testing with imipenem-relebactam using KPC-producing clinical isolates of Enterobacteriaceae...
April 2, 2018: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29530851/inactivation-of-the-pseudomonas-derived-cephalosporinase-3-pdc-3-by-relebactam
#6
Melissa D Barnes, Christopher R Bethel, Jim Alsop, Scott A Becka, Joseph D Rutter, Krisztina M Papp-Wallace, Robert A Bonomo
Pseudomonas aeruginosa is a prevalent and life-threatening Gram-negative pathogen. Pseudomonas -derived cephlosporinase (PDC) is the major inducible cephalosporinase in P. aeruginosa In this investigation, we show that relebactam, a diazabicyclooctane β-lactamase inhibitor, potently inactivates PDC-3, with a k 2 / K of 41,400 M-1 s-1 and a k off of 0.00095 s-1 Relebactam restored susceptibility to imipenem in 62% of multidrug-resistant P. aeruginosa clinical isolates, while only 21% of isolates were susceptible to imipenem-cilastatin alone...
May 2018: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29456071/evaluation-of-sensititre-broth-microdilution-plate-for-determining-the-susceptibility-of-carbapenem-resistant-klebsiella-pneumoniae-to-polymyxins
#7
Sandra S Richter, James Karichu, Joshua Otiso, Hillary Van Heule, George Keller, Eric Cober, Laura J Rojas, Andrea M Hujer, Kristine M Hujer, Steve Marshall, Frederico Perez, Susan D Rudin, T Nicholas Domitrovic, Keith S Kaye, Robert Salata, David van Duin, Robert A Bonomo
Colistin and polymyxin B MICs were determined for 106 carbapenem-resistant Klebsiella pneumoniae (CR-Kp) isolates using Sensititre Research Use Only GNX2F plates (Thermo Fisher) and compared to CLSI broth macrodilution (BMD) as the reference method. For colistin, EUCAST breakpoints were applied and testing of isolates with very major (VM) errors was repeated in duplicate by both methods to determine a majority result. Essential agreement (MIC ± one dilution) of GNX2F with the reference method was 97.1% for polymyxin B and 92...
May 2018: Diagnostic Microbiology and Infectious Disease
https://www.readbyqxmd.com/read/29456042/evidence-to-improve-the-treatment-of-infections-caused-by-carbapenem-resistant-gram-negative-bacteria
#8
Federico Perez, Robert A Bonomo
No abstract text is available yet for this article.
April 2018: Lancet Infectious Diseases
https://www.readbyqxmd.com/read/29444247/infectious-diseases-physicians-leading-the-way-in-antimicrobial-stewardship
#9
Belinda Ostrowsky, Ritu Banerjee, Robert A Bonomo, Sara E Cosgrove, Lisa Davidson, Shira Doron, David N Gilbert, Amanda Jezek, John B Lynch, Edward J Septimus, Javeed Siddiqui, Nicole M Iovine
No abstract text is available yet for this article.
March 19, 2018: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
https://www.readbyqxmd.com/read/29439972/probing-the-mechanism-of-inactivation-of-the-fox-4-cephamycinase-by-avibactam
#10
Michiyoshi Nukaga, Krisztina M Papp-Wallace, Tyuji Hoshino, Scott T Lefurgy, Christopher R Bethel, Melissa D Barnes, Elise T Zeiser, J Kristie Johnson, Robert A Bonomo
Ceftazidime-avibactam is a "second-generation" β-lactam-β-lactamase inhibitor combination that is effective against Enterobacteriaceae expressing class A extended-spectrum β-lactamases, class A carbapenemases, and/or class C cephalosporinases. Knowledge of the interactions of avibactam, a diazabicyclooctane with different β-lactamases, is required to anticipate future resistance threats. FOX family β-lactamases possess unique hydrolytic properties with a broadened substrate profile to include cephamycins, partly as a result of an isoleucine at position 346, instead of the conserved asparagine found in most AmpCs...
May 2018: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29414265/new-molecular-diagnostic-approaches-to-bacterial-infections-and-antibacterial-resistance
#11
Ephraim L Tsalik, Robert A Bonomo, Vance G Fowler
Recent advances in the field of infectious disease diagnostics have given rise to a number of host- and pathogen-centered diagnostic approaches. Most diagnostic approaches in contemporary infectious disease focus on pathogen detection and characterization. Host-focused diagnostics have recently emerged and are based on detecting the activation of biological pathways that are highly specific to the type of infecting pathogen (e.g., viral, bacterial, protozoan, fungal). Although this progress is encouraging, it is unlikely that any single diagnostic platform will fully address the clinician's need for actionable data with short turnaround times in all settings...
January 29, 2018: Annual Review of Medicine
https://www.readbyqxmd.com/read/29337085/disc-describing-infections-of-the-spine-treated-with-ceftaroline
#12
Richard R Watkins, George Yendewa, Steven D Burdette, Sophia Horattas, Nairmeen Awad Haller, Caroline Mangira, Robert A Salata, Robert A Bonomo
OBJECTIVES: Infections of the spine lead to considerable morbidity and a high cost to the global healthcare system. Currently, evidence for using ceftaroline, an advanced-generation cephalosporin active against methicillin-resistant Staphylococcus aureus (MRSA), in spine infections is limited. METHODS: Describing Infections of the Spine treated with Ceftaroline (DISC) is a multicentre, retrospective, cohort study that evaluated ceftaroline for treating spine infections...
January 11, 2018: Journal of Global Antimicrobial Resistance
https://www.readbyqxmd.com/read/29310479/therapies-for-multidrug-resistant-and-extensively-drug-resistant-non-fermenting-gram-negative-bacteria-causing-nosocomial-infections-a-perilous-journey-toward-molecularly-targeted-therapy
#13
Nadim G El Chakhtoura, Elie Saade, Alina Iovleva, Mohamad Yasmin, Brigid Wilson, Federico Perez, Robert A Bonomo
Non-fermenting Gram-negative bacilli are at the center of the antimicrobial resistance epidemic. Acinetobacter baumannii and Pseudomonas aeruginosa are both designated with a threat level to human health of 'serious' by the Centers for Disease Control and Prevention. Two other major non-fermenting Gram-negative bacilli, Stenotrophomonas maltophilia and Burkholderia cepacia complex, while not as prevalent, have devastating effects on vulnerable populations, such as those with cystic fibrosis, as well as immunosuppressed or hospitalized patients...
February 2018: Expert Review of Anti-infective Therapy
https://www.readbyqxmd.com/read/29274468/molecular-characterization-of-carbapenem-resistant-enterobacter-cloacae-complex-in-colombia-bla-kpc-and-the-changing-landscape
#14
Elsa De La Cadena, Adriana Correa, Juan Sebastián Muñoz, Laura J Rojas, Cristhian Hernández-Gómez, Christian Pallares, Federico Perez, Robert A Bonomo, Maria V Villegas
OBJECTIVES: To examine the population structure of representative carbapenem resistant Enterobacter cloacae complex (CR-Ecl) isolates from 8 different Colombian regions and to characterize their asociated β-lactamases. METHODS: Twenty-eight CR-Ecl isolates collected in Colombia between 2009 and 2013 through the Colombian Nosocomial Network were included. Antimicrobial susceptibility testing was performed by broth microdilution. Molecular detection of carbapenemases and extended-spectrum β-lactamases (ESBL), and the presence of Tn4401 was evaluated by PCR and sequencing...
December 20, 2017: Journal of Global Antimicrobial Resistance
https://www.readbyqxmd.com/read/29229762/multiple-substitutions-lead-to-increased-loop-flexibility-and-expanded-specificity-in-acinetobacter-baumannii-carbapenemase-oxa-239
#15
Thomas M Harper, Cynthia M June, Magdalena A Taracila, Robert A Bonomo, Rachel A Powers, David A Leonard
OXA-239 is a class D carbapenemase isolated from an Acinetobacter baumannii strain found in Mexico. This enzyme is a variant of OXA-23 with three amino acid substitutions in or near the active site. These substitutions cause OXA-239 to hydrolyze late-generation cephalosporins and the monobactam aztreonam with greater efficiency than OXA-23. OXA-239 activity against the carbapenems doripenem and imipenem is reduced ∼3-fold and 20-fold, respectively. Further analysis demonstrated that two of the substitutions (P225S and D222N) are largely responsible for the observed alteration of kinetic parameters, while the third (S109L) may serve to stabilize the protein...
January 11, 2018: Biochemical Journal
https://www.readbyqxmd.com/read/29181422/carbapenem-resistant-enterobacteriaceae-infections-in-patients-on-renal-replacement-therapy
#16
Brandon Eilertson, Eric Cober, Sandra S Richter, Federico Perez, Robert A Salata, Robert C Kalayjian, Richard R Watkins, Yohei Doi, Keith S Kaye, Scott Evans, Vance G Fowler, Robert A Bonomo, Jack DeHovitz, Barry Kreiswirth, David van Duin
Background: Patients on chronic intermittent renal replacement therapy (RRT) are at risk for infection with carbapenem-resistant Enterobacteriaceae (CRE). However, the impact of RRT on outcomes after CRE infections remains to be defined. Here we perform a comparison of outcomes for CRE-infected patients with preserved renal function compared with CRE-infected patients on RRT. Methods: Cases and controls were defined from a prospective cohort of CRE-infected patients from the Consortium on Resistance against Carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE)...
2017: Open Forum Infectious Diseases
https://www.readbyqxmd.com/read/29165604/carbapenemase-producing-organisms-a-global-scourge
#17
Robert A Bonomo, Eileen M Burd, John Conly, Brandi M Limbago, Laurent Poirel, Julie A Segre, Lars F Westblade
The dramatic increase in the prevalence and clinical impact of infections caused by bacteria producing carbapenemases is a global health concern. Carbapenemase production is especially problematic when encountered in members of the family Enterobacteriaceae. Due to their ability to readily spread and colonize patients in health care environments, preventing the transmission of these organisms is a major public health initiative and coordinated international effort is needed to contain the risk of infection...
October 16, 2017: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
https://www.readbyqxmd.com/read/29144725/inhibition-of-acinetobacter-derived-cephalosporinase-exploring-the-carboxylate-recognition-site-using-novel-%C3%AE-lactamase-inhibitors
#18
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 β-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 β-lactams, we designed, synthesized, and characterized six derivatives of S02030 (3a)...
March 9, 2018: ACS Infectious Diseases
https://www.readbyqxmd.com/read/29144724/structure-based-analysis-of-boronic-acids-as-inhibitors-of-acinetobacter-derived-cephalosporinase-7-a-unique-class-c-%C3%AE-lactamase
#19
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 mediated by class C β-lactamases known as Acinetobacter-derived cephalosporinases (ADCs). ADCs are unaffected by clinically used β-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...
March 9, 2018: ACS Infectious Diseases
https://www.readbyqxmd.com/read/29133567/risk-factors-and-outcomes-associated-with-multidrug-resistant-acinetobacter-baumannii-upon-intensive-care-unit-admission
#20
Natalia Blanco, Anthony D Harris, Clare Rock, J Kristie Johnson, Lisa Pineles, Robert A Bonomo, Arjun Srinivasan, Melinda M Pettigrew, Kerri A Thom
Multidrug-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 upon admission to the intensive care unit (ICU) over a 5-year period and to identify risk factors and outcomes associated with colonization. A retrospective cohort analysis of patients admitted to the medical intensive care unit (MICU) and surgical intensive care unit (SICU) at the University of Maryland Medical Center from May 2005 to September 2009 was performed using perirectal surveillance cultures on admission...
January 2018: Antimicrobial Agents and Chemotherapy
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