scholarly journals Potential for Reduction of Streptogramin A Resistance Revealed by Structural Analysis of Acetyltransferase VatA

2014 ◽  
Vol 58 (12) ◽  
pp. 7083-7092 ◽  
Author(s):  
Peter J. Stogios ◽  
Misty L. Kuhn ◽  
Elena Evdokimova ◽  
Patrice Courvalin ◽  
Wayne F. Anderson ◽  
...  
Keyword(s):  
Large Family ◽  
Structural Determinants ◽  
Conserved Residues ◽  
Content Type ◽  
Virginiamycin M1 ◽  
Group A ◽  
Vancomycin Resistant ◽  
Binding Determinants ◽  
Molecular Framework

ABSTRACTCombinations of group A and B streptogramins (i.e., dalfopristin and quinupristin) are “last-resort” antibiotics for the treatment of infections caused by Gram-positive pathogens, including methicillin-resistantStaphylococcus aureusand vancomycin-resistantEnterococcus faecium. Resistance to streptogramins has arisen via multiple mechanisms, including the deactivation of the group A component by the large family of virginiamycinO-acetyltransferase (Vat) enzymes. Despite the structural elucidation performed for the VatD acetyltransferase, which provided a general molecular framework for activity, a detailed characterization of the essential catalytic and antibiotic substrate-binding determinants in Vat enzymes is still lacking. We have determined the crystal structure ofS. aureusVatA inapo, virginiamycin M1- and acetyl-coenzyme A (CoA)-bound forms and provide an extensive mutagenesis and functional analysis of the structural determinants required for catalysis and streptogramin A recognition. Based on an updated genomic survey across the Vat enzyme family, we identified key conserved residues critical for VatA activity that are not part of theO-acetylation catalytic apparatus. Exploiting such constraints of the Vat active site may lead to the development of streptogramin A compounds that evade inactivation by Vat enzymes while retaining binding to their ribosomal target.

scholarly journals 4-Amino-2-Sulfanylbenzoic Acid as a Potent Subclass B3 Metallo-β-Lactamase-Specific Inhibitor Applicable for Distinguishing Metallo-β-Lactamase Subclasses

2019 ◽  
Vol 63 (10) ◽  
Author(s):  
Jun-ichi Wachino ◽  
Reo Kanechi ◽  
Erina Nishino ◽  
Marie Mochizuki ◽  
Wanchun Jin ◽  
...  
Keyword(s):  
Specific Inhibitor ◽  
Carbapenem Resistance ◽  
Resistance Mechanisms ◽  
Health Concern ◽  
Conserved Residues ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Promising Strategy ◽  
Starting Point

ABSTRACT The number of cases of infection with carbapenem-resistant Enterobacteriaceae (CRE) has been increasing and has become a major clinical and public health concern. Production of metallo-β-lactamases (MBLs) is one of the principal carbapenem resistance mechanisms in CRE. Therefore, developing MBL inhibitors is a promising strategy to overcome the problems of carbapenem resistance conferred by MBLs. To date, the development and evaluation of MBL inhibitors have focused on subclass B1 MBLs but not on B3 MBLs. In the present study, we searched for B3 MBL (specifically, SMB-1) inhibitors and found thiosalicylic acid (TSA) to be a potent inhibitor of B3 SMB-1 MBL (50% inhibitory concentration [IC50], 0.95 μM). TSA inhibited the purified SMB-1 to a considerable degree but was not active against Escherichia coli cells producing SMB-1, as the meropenem (MEM) MIC for the SMB-1 producer was only slightly reduced with TSA. We then introduced a primary amine to TSA and synthesized 4-amino-2-sulfanylbenzoic acid (ASB), which substantially reduced the MEM MICs for SMB-1 producers. X-ray crystallographic analyses revealed that ASB binds to the two zinc ions, Ser221, and Thr223 at the active site of SMB-1. These are ubiquitously conserved residues across clinically relevant B3 MBLs. ASB also significantly inhibited other B3 MBLs, including AIM-1, LMB-1, and L1. Therefore, the characterization of ASB provides a starting point for the development of optimum B3 MBL inhibitors.

scholarly journals Changes in epidemiologic characteristics and antimicrobial resistance of Streptococcus pyogenes isolated over 10 years from Japanese children with pharyngotonsillitis

2020 ◽  
Vol 69 (3) ◽  
pp. 443-450
Author(s):  
Kimiko Ubukata ◽  
Takeaki Wajima ◽  
Miyuki Morozumi ◽  
Megumi Sakuma ◽  
Takeshi Tajima ◽  
...  
Keyword(s):  
Streptococcus Pyogenes ◽  
Antibiotic Susceptibility ◽  
Rapid Identification ◽  
Specific Sequence ◽  
Content Type ◽  
Group A ◽  
Sequence Types ◽  
Identification And Characterization ◽  
Epidemiologic Characteristics

Introduction. Pharyngotonsillitis caused by Streptococcus pyogenes (group A streptococci, or GAS) is among the most common infections treated with antibiotics in pediatric patients. Aim. This study aimed to analyse changes in molecular epidemiology and antibiotic susceptibility among GAS isolates in three study periods spanning 10 years. Methodology. GAS isolated from paediatric patients with pharyngotonsillitis during Period I (mid-2007 to 2008, n=235), Period II (2012, n=210), and Period III (2018, n=189) were analysed for emm type, multilocus sequence type (MLST), antibiotic susceptibility, and macrolide (ML)- and quinolone (QL)-resistance genes. Results. Over 20 % of isolates represented emm1 and emm12 types, remaining common in all three periods. Among other emm types, emm4 was common in Period I, emm28 and emm89 in Period II, and emm3 and emm89 in Period III. All isolates remained highly susceptible to penicillins and cephalosporins. Isolates possessing mefA, ermA, or ermB genes mediating ML resistance increased from 34.9 % in Period I to 60.9 % in Period II, but fell to 27.5 % in Period III. QL-resistant isolates with amino acid substitutions affecting ParC and/or GyrA gradually increased from 11.5 to 14.3 %. Specific sequence types identified by MLST and emm typing were associated closely with ML or QL resistance. Conclusion. Our findings indicate that even in ambulatory care, antibiotic choice for these infections should be based on rapid identification and characterization of causative pathogens.

scholarly journals Characterization of Class IIa Bacteriocin Resistance in Enterococcus faecium

2017 ◽  
Vol 61 (4) ◽  
Author(s):  
Kathryn Geldart ◽  
Yiannis N. Kaznessis
Keyword(s):  
Enterococcus Faecium ◽  
Carbon Sources ◽  
Content Type ◽  
Development Of Resistance ◽  
Vancomycin Resistant Enterococci ◽  
Reverse Transcription Quantitative Pcr ◽  
Potential Alternative ◽  
Vancomycin Resistant ◽  
Enterocin A

ABSTRACT Vancomycin-resistant enterococci, particularly resistant Enterococcus faecium, pose an escalating threat in nosocomial environments because of their innate resistance to many antibiotics, including vancomycin, a treatment of last resort. Many class IIa bacteriocins strongly target these enterococci and may offer a potential alternative for the management of this pathogen. However, E. faecium's resistance to these peptides remains relatively uncharacterized. Here, we explored the development of resistance of E. faecium to a cocktail of three class IIa bacteriocins: enterocin A, enterocin P, and hiracin JM79. We started by quantifying the frequency of resistance to these peptides in four clinical isolates of E. faecium. We then investigated the levels of resistance of E. faecium 6E6 mutants as well as their fitness in different carbon sources. In order to elucidate the mechanism of resistance of E. faecium to class IIa bacteriocins, we completed whole-genome sequencing of resistant mutants and performed reverse transcription-quantitative PCR (qRT-PCR) of a suspected target mannose phosphotransferase (ManPTS). We then verified this ManPTS's role in bacteriocin susceptibility by showing that expression of the ManPTS in Lactococcus lactis results in susceptibility to the peptide cocktail. Based on the evidence found from these studies, we conclude that, in accord with other studies in E. faecalis and Listeria monocytogenes, resistance to class IIa bacteriocins in E. faecium 6E6 is likely caused by the disruption of a particular ManPTS, which we believe we have identified.

scholarly journals Isolation and characterization of novel glycolipids with blood group A-related structures: galactosyl-A and sialosylgalactosyl-A.

1987 ◽  
Vol 262 (29) ◽  
pp. 14228-14234
Author(s):  
H Clausen ◽  
S B Levery ◽  
E D Nudelman ◽  
M Stroud ◽  
M E Salyan ◽  
...  
Keyword(s):  
Blood Group ◽  
Blood Group A ◽  
Isolation And Characterization ◽  
Group A

scholarly journals Characterization of Charge States in Conducting Organic Nanoparticles by X-ray Photoemission Spectroscopy

Materials ◽  
2021 ◽  
Vol 14 (8) ◽  
pp. 2058
Author(s):  
Jordi Fraxedas ◽  
Antje Vollmer ◽  
Norbert Koch ◽  
Dominique de Caro ◽  
Kane Jacob ◽  
...  
Keyword(s):  
Partial Oxidation ◽  
Chemical Shifts ◽  
Large Family ◽  
Photoemission Spectroscopy ◽  
Intrinsic Structure ◽  
X Ray ◽  
Level Lines ◽  
Donor And Acceptor ◽  
Electronic Configurations

The metallic and semiconducting character of a large family of organic materials based on the electron donor molecule tetrathiafulvalene (TTF) is rooted in the partial oxidation (charge transfer or mixed valency) of TTF derivatives leading to partially filled molecular orbital-based electronic bands. The intrinsic structure of such complexes, with segregated donor and acceptor molecular chains or planes, leads to anisotropic electronic properties (quasi one-dimensional or two-dimensional) and morphology (needle-like or platelet-like crystals). Recently, such materials have been synthesized as nanoparticles by intentionally frustrating the intrinsic anisotropic growth. X-ray photoemission spectroscopy (XPS) has emerged as a valuable technique to characterize the transfer of charge due to its ability to discriminate the different chemical environments or electronic configurations manifested by chemical shifts of core level lines in high-resolution spectra. Since the photoemission process is inherently fast (well below the femtosecond time scale), dynamic processes can be efficiently explored. We determine here the fingerprint of partial oxidation on the photoemission lines of nanoparticles of selected TTF-based conductors.

Burma Drinx Group (A): Strategizing for CEO Succession in a Family Business

2021 ◽  
Vol 10 (1) ◽  
pp. 16-32
Author(s):  
Daniel Degravel ◽  
Christina Hui Min Tun
Keyword(s):  
Family Business ◽  
Large Family ◽  
Asian Country ◽  
Business Environment ◽  
Decision Makers ◽  
External Information ◽  
Ceo Succession ◽  
Academic Literature ◽  
Group A ◽  
Evolving Context

Burma Drinx Group, a large family-owned conglomerate in Myanmar, an Asian country in economic and political transition, is about to reinvent itself to achieve success and adaptation to its evolving context. Based on internal and external information about the firm, the case states the challenges and issues that Burma Drinx Group (thereafter BDG) is experiencing as a family-owned conglomerate operating in a ‘non-friendly’ business environment and in a turbulent political and economic context. It focuses on the group CEO Aung Win’s succession. The reader is invited to understand the specificities of BDG’s internal environment, and to manage the idiosyncrasies of this family business conglomerate regarding CEO Win’s succession. Beyond the succession issue, BDG’s decision-makers face critical challenges for the future and have to make bold and courageous decisions to build on the success of the organization. The case proposes a consulting-case style where analysis and reflection are required to understand the challenges and to provide relevant solutions to the top management of the company. Material from the academic literature about succession is offered as a resource to the reader.

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