Class D β-lactamases

2020 ◽  
Author(s):  
Eun-Jeong Yoon ◽  
Seok Hoon Jeong
Keyword(s):  
Functional Groups ◽  
Active Site ◽  
Active Sites ◽  
Amino Acid Substitutions ◽  
Family Needs ◽  
Intrinsic Resistance ◽  
Class D ◽  
The Family ◽  
Environmental Bacteria ◽  
Clinically Significant

Abstract Class D β-lactamases are composed of 14 families and the majority of the member enzymes are included in the OXA family. The genes for class D β-lactamases are frequently identified in the chromosome as an intrinsic resistance determinant in environmental bacteria and a few of these are found in mobile genetic elements carried by clinically significant pathogens. The most dominant OXA family among class D β-lactamases is superheterogeneous and the family needs to have an updated scheme for grouping OXA subfamilies through phylogenetic analysis. The OXA enzymes, even the members within a subfamily, have a diverse spectrum of resistance. Such varied activity could be derived from their active sites, which are distinct from those of the other serine β-lactamases. Their substrate profile is determined according to the size and position of the P-, Ω- and β5–β6 loops, assembling the active-site channel, which is very hydrophobic. Also, amino acid substitutions occurring in critical structures may alter the range of hydrolysed substrates and one subfamily could include members belonging to several functional groups. This review aims to describe the current class D β-lactamases including the functional groups, occurrence types (intrinsic or acquired) and substrate spectra and, focusing on the major OXA family, a new model for subfamily grouping will be presented.

scholarly journals Multiple substitutions lead to increased loop flexibility and expanded specificity in Acinetobacter baumannii carbapenemase OXA-239

2018 ◽  
Vol 475 (1) ◽  
pp. 273-288 ◽  
Author(s):  
Thomas M. Harper ◽  
Cynthia M. June ◽  
Magdalena A. Taracila ◽  
Robert A. Bonomo ◽  
Rachel A. Powers ◽  
...  
Keyword(s):  
Amino Acid ◽  
Acinetobacter Baumannii ◽  
Active Site ◽  
Active Sites ◽  
Protein Structures ◽  
Amino Acid Substitutions ◽  
The Third ◽  
Class D ◽  
Late Generation ◽  
Loop Flexibility

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. Structures of OXA-239 with cefotaxime, doripenem and imipenem bound as acyl-intermediates were determined. These structures reveal that OXA-239 has increased flexibility in a loop that contains P225S and D222N. When carbapenems are bound, the conformation of this loop is essentially identical with that observed previously for OXA-23, with a narrow active site that makes extensive contacts to the ligand. When cefotaxime is bound, the loop can adopt a different conformation that widens the active site to allow binding of that bulky drug. This alternate conformation is made possible by P225S and further stabilized by D222N. Taken together, these results suggest that the three substitutions were selected to expand the substrate specificity profile of OXA-23 to cephalosporins and monobactams. The loss of activity against imipenem, however, suggests that there may be limits to the plasticity of class D enzymes with regard to evolving active sites that can effectively bind multiple classes of β-lactam drugs.

scholarly journals Active-Site Plasticity Is Essential to Carbapenem Hydrolysis by OXA-58 Class D β-Lactamase of Acinetobacter baumannii

2015 ◽  
Vol 60 (1) ◽  
pp. 75-86 ◽  
Author(s):  
Shivendra Pratap ◽  
Madhusudhanarao Katiki ◽  
Preet Gill ◽  
Pravindra Kumar ◽  
Dasantila Golemi-Kotra
Keyword(s):  
Crystal Structure ◽  
Acinetobacter Baumannii ◽  
Active Site ◽  
Active Sites ◽  
Multidrug Resistant ◽  
Crystal Structure Analysis ◽  
Content Type ◽  
Class D ◽  
Enzyme Species ◽  
Hydroxyethyl Group

ABSTRACTCarbapenem-hydrolyzing class D β-lactamases (CHDLs) are a subgroup of class D β-lactamases, which are enzymes that hydrolyze β-lactams. They have attracted interest due to the emergence of multidrug-resistantAcinetobacter baumannii, which is not responsive to treatment with carbapenems, the usual antibiotics of choice for this bacterium. Unlike other class D β-lactamases, these enzymes efficiently hydrolyze carbapenem antibiotics. To explore the structural requirements for the catalysis of carbapenems by these enzymes, we determined the crystal structure of the OXA-58 CHDL ofA. baumanniifollowing acylation of its active-site serine by a 6α-hydroxymethyl penicillin derivative that is a structural mimetic for a carbapenem. In addition, several point mutation variants of the active site of OXA-58, as identified by the crystal structure analysis, were characterized kinetically. These combined studies confirm the mechanistic relevance of a hydrophobic bridge formed over the active site. This structural feature is suggested to stabilize the hydrolysis-productive acyl-enzyme species formed from the carbapenem substrates of this enzyme. Furthermore, our structural studies provide strong evidence that the hydroxyethyl group of carbapenems samples different orientations in the active sites of CHDLs, and the optimum orientation for catalysis depends on the topology of the active site allowing proper closure of the active site. We propose that CHDLs use the plasticity of the active site to drive the mechanism of carbapenem hydrolysis toward efficiency.

scholarly journals Interactions of Ceftobiprole with β-Lactamases from Molecular Classes A to D

2007 ◽  
Vol 51 (9) ◽  
pp. 3089-3095 ◽  
Author(s):  
Anne Marie Queenan ◽  
Wenchi Shang ◽  
Malgosia Kania ◽  
Malcolm G. P. Page ◽  
Karen Bush
Keyword(s):  
Functional Groups ◽  
Hydrolytic Stability ◽  
Enterobacter Cloacae ◽  
Class A ◽  
Extended Spectrum ◽  
Class D ◽  
The Family ◽  
Class B ◽  
The Common ◽  
Antibacterial Spectrum

ABSTRACT The interactions of ceftobiprole with purified β-lactamases from molecular classes A, B, C, and D were determined and compared with those of benzylpenicillin, cephaloridine, cefepime, and ceftazidime. Enzymes were selected from functional groups 1, 2a, 2b, 2be, 2d, 2e, and 3 to represent β-lactamases from organisms within the antibacterial spectrum of ceftobiprole. Ceftobiprole was refractory to hydrolysis by the common staphylococcal PC1 β-lactamase, the class A TEM-1 β-lactamase, and the class C AmpC β-lactamase but was labile to hydrolysis by class B, class D, and class A extended-spectrum β-lactamases. Cefepime and ceftazidime followed similar patterns. In most cases, the hydrolytic stability of a substrate correlated with the MIC for the producing organism. Ceftobiprole and cefepime generally had lower MICs than ceftazidime for AmpC-producing organisms, particularly AmpC-overexpressing Enterobacter cloacae organisms. However, all three cephalosporins were hydrolyzed very slowly by AmpC cephalosporinases, suggesting that factors other than β-lactamase stability contribute to lower ceftobiprole and cefepime MICs against many members of the family Enterobacteriaceae.

Catalytic Resonance Theory: Parallel Reaction Pathway Control

2019 ◽  
Author(s):  
M. Alexander Ardagh ◽  
Manish Shetty ◽  
Anatoliy Kuznetsov ◽  
Qi Zhang ◽  
Phillip Christopher ◽  
...  
Keyword(s):  
Chemical Reactions ◽  
Active Site ◽  
Active Sites ◽  
Reaction Pathway ◽  
Control Strategies ◽  
Oscillation Amplitude ◽  
Catalytic Performance ◽  
Parallel Reaction ◽  
Resonance Theory ◽  
Static Conditions

Catalytic enhancement of chemical reactions via heterogeneous materials occurs through stabilization of transition states at designed active sites, but dramatically greater rate acceleration on that same active site is achieved when the surface intermediates oscillate in binding energy. The applied oscillation amplitude and frequency can accelerate reactions orders of magnitude above the catalytic rates of static systems, provided the active site dynamics are tuned to the natural frequencies of the surface chemistry. In this work, differences in the characteristics of parallel reactions are exploited via selective application of active site dynamics (0 < ΔU < 1.0 eV amplitude, 10<sup>-6</sup> < f < 10<sup>4</sup> Hz frequency) to control the extent of competing reactions occurring on the shared catalytic surface. Simulation of multiple parallel reaction systems with broad range of variation in chemical parameters revealed that parallel chemistries are highly tunable in selectivity between either pure product, even when specific products are not selectively produced under static conditions. Two mechanisms leading to dynamic selectivity control were identified: (i) surface thermodynamic control of one product species under strong binding conditions, or (ii) catalytic resonance of the kinetics of one reaction over the other. These dynamic parallel pathway control strategies applied to a host of chemical conditions indicate significant potential for improving the catalytic performance of many important industrial chemical reactions beyond their existing static performance.

PEMANFAATAN PENDAPATAN PEDAGANG BAKSO IKAN TUNA KELILING DI KOTA AMBON

2018 ◽  
Vol 2 (2) ◽  
pp. 85-96
Author(s):  
Hardianti Abubakar ◽  
Yolanda MTN Apituley ◽  
Lilian M. Soukotta
Keyword(s):  
High School ◽  
School Level ◽  
Family Needs ◽  
Average Income ◽  
High School Level ◽  
Tuna Fish ◽  
Fish Meat ◽  
The Family ◽  
Personal Needs ◽  
Origin Area

As a form of diversified processed fish meat, tuna meatball is very popular to people in Ambon. This type of food is sold by traders from Java by walking or cycling. Difficulties living in the origin area require traders to leave their families and go out looking for jobs in other areas with hopes that the family needs are met. The purpose of this research is to analyze (1). Characteristics of mobile tuna meatball traders in Ambon, (2). The amount of income received by mobile tuna meatball traders in Ambon, and (3). Percentage income utilized by the mobile tuna meatball traders either in family or personal needs. The study was conducted by survey and data obtained through interviews and observations from May to October 2018. The results show that the average age of meatball traders was between <25-65 yo, having education in junior and senior high school level, with the highest number of dependants 1-2 people and <5 years trading experience. The average income of tuna fish meatball traders is Rp. 4,747,231, - which is used for personal and family needs. Seven  traders use more than 50% for family needs and the rest for personal needs, while six traders utilize more than 60 % for personal needs and the rest for family needs.

Quality of Life (QOL) of Balinese Women Working in Spa Tourism Industry

2015 ◽  
Vol 1 (1) ◽  
pp. 13
Author(s):  
Putu Sucita Yanthy ◽  
Luh Gede Leli Kusuma Dewi ◽  
W. Citra Juwitasari
Keyword(s):  
Quality Of Life ◽  
Tourism Industry ◽  
Family Needs ◽  
Interesting Phenomenon ◽  
Tourist Destinations ◽  
Foreign Countries ◽  
The Family ◽  
Two Factors ◽  
Material Factor

Bali is one of spa tourist destinations having various categories of spas and spa treatments, and the most important is the spa therapists. Spa development becomes an interesting phenomenon to be studied when it is associated with an involvement of Balinese women as spa therapists in foreign countries. The world’s demand for Balinese spa therapists has become the motivation of women to work in this area. The work and life of Balinese spa therapists while they are working in foreign countries serve as parameters to know their quality of life, and these parameters are also the main focus of this study. Through in-depth interviews and questionnaires distributed to 20 therapists it was found out that 85 percent of them have revealed an improvement in their quality of life that is influenced by two factors: the material and intimacy factors. The material factor in question refers to the economic improvement of the family as they could earn enough income to cover their family needs. The intimacy factor in question refers to closeness and a sense of solidarity fostered while they are working abroad and the relationship within the family. This study concludes that the most important part of the development of spa in Bali is its female Balinese spa therapists due to the image that Balinese women working as spa therapists are loyal, hard-working and honest making them in demand among tourists who are seeking spa treatments. Being a spa therapist can improve their quality of life, which means that subjectively both material and intimacy factors are the aspects that affect the quality of life of the Balinese spa therapists.

Gender Moderates the Association Between Exposure to Interpersonal Violence and Intermittent Explosive Disorder Diagnosis

2021 ◽  
pp. 088626052110139
Author(s):  
Lynette C. Krick ◽  
Mitchell E. Berman ◽  
Michael S. McCloskey ◽  
Emil F. Coccaro ◽  
Jennifer R. Fanning
Keyword(s):  
Risk Factor ◽  
Aggressive Behavior ◽  
Interpersonal Violence ◽  
Men And Women ◽  
Affective Dysregulation ◽  
Intermittent Explosive Disorder ◽  
The Family ◽  
History Of ◽  
Clinically Significant ◽  
The Relationship

Exposure to interpersonal violence (EIV) is a prevalent risk-factor for aggressive behavior; however, it is unclear whether the effect of EIV on clinically significant aggressive behavior is similar across gender. We examined whether gender moderates the association between experiencing and witnessing interpersonal violence and the diagnosis of intermittent explosive disorder (IED). We also examined potential pathways that might differentially account for the association between EIV and IED in men and women, including emotion regulation and social information processing (SIP). Adult men and women ( N = 582), who completed a semistructured clinical interview for syndromal and personality disorders, were classified as healthy controls (HC; n = 118), psychiatric controls (PC; n = 146) or participants with an IED diagnosis ( n = 318). Participants also completed the life history of experienced aggression (LHEA) and life history of witnessed aggression (Lhwa) structured interview and self-report measures of emotion regulation and SIP. Men reported more EIV over the lifetime. In multiple logistic regression analysis, experiencing and witnessing aggression within the family and experiencing aggression outside the family were associated with lifetime IED diagnosis. We found that the relationship between EIV and IED was stronger in women than in men. Affective dysregulation mediated certain forms of EIV, and this relation was observed in both men and women. SIP biases did not mediate the relation between EIV and IED. EIV across the lifespan is a robust risk factor for recurrent, clinically significant aggressive behavior (i.e., IED). However, the relationship between EIV and IED appears to be stronger in women. Further, this relation appears partially mediated by affective dysregulation.

scholarly journals How to talk with the family of a dying patient: anger to understanding, rage to compassion, loss to acceptance

2021 ◽  
pp. bmjspcare-2021-002971
Author(s):  
Moshe Y Flugelman
Keyword(s):  
Goal Setting ◽  
Stressful Situation ◽  
Family Needs ◽  
The Third ◽  
Single Entity ◽  
The Family ◽  
Patient Families ◽  
The Difference ◽  
Dying Patient

Informing families about the impending or actual death of their relatives is one of the most challenging and complex tasks a physician may face. The following article describes goal setting and provides five roles/recommendations for conducting the encounter with patient families regarding the imminent or actual death of their relatives. Importantly, the encounter should be family-centred, and the physician should be highly attentive to family needs. The following roles should be applied based on family needs and should not be sequential as numbered. The first and basic role is to inform the family at the earliest possible time and as often as possible. The second goal of the physician is to convey to the family that their relative received the needed therapy during his hospitalisation or in the community. The third goal of the physician is to help the family reach acceptance of the death of their relative and leave the hospital having moved beyond anger and bargaining. The fourth goal of the physician during the encounters is to reduce or alleviate guilt by stating that nothing could have changed the course of the disease and that all efforts were made to save the patient. The fifth role of the physician is to try and help the family as a single entity and maintain their unity during this stressful situation. Following these roles/methods will help families in the stressful situation and will create the difference between anger and understanding, rage and compassion, and loss and acceptance.

scholarly journals Involvement of loop 5 lysine residues and the N-terminal β-hairpin of the ribotoxin hirsutellin A on its insecticidal activity

2016 ◽  
Vol 397 (2) ◽  
pp. 135-145 ◽  
Author(s):  
Miriam Olombrada ◽  
Lucía García-Ortega ◽  
Javier Lacadena ◽  
Mercedes Oñaderra ◽  
José G. Gavilanes ◽  
...  
Keyword(s):  
Active Sites ◽  
Structural Changes ◽  
The Other ◽  
Spatial Proximity ◽  
Ribonucleolytic Activity ◽  
The Family ◽  
Lysine Residues ◽  
Hirsutella Thompsonii ◽  
Close Spatial Proximity ◽  
High Degree

Abstract Ribotoxins are cytotoxic members of the family of fungal extracellular ribonucleases best represented by RNase T1. They share a high degree of sequence identity and a common structural fold, including the geometric arrangement of their active sites. However, ribotoxins are larger, with a well-defined N-terminal β-hairpin, and display longer and positively charged unstructured loops. These structural differences account for their cytotoxic properties. Unexpectedly, the discovery of hirsutellin A (HtA), a ribotoxin produced by the invertebrate pathogen Hirsutella thompsonii, showed how it was possible to accommodate these features into a shorter amino acid sequence. Examination of HtA N-terminal β-hairpin reveals differences in terms of length, charge, and spatial distribution. Consequently, four different HtA mutants were prepared and characterized. One of them was the result of deleting this hairpin [Δ(8-15)] while the other three affected single Lys residues in its close spatial proximity (K115E, K118E, and K123E). The results obtained support the general conclusion that HtA active site would show a high degree of plasticity, being able to accommodate electrostatic and structural changes not suitable for the other previously known larger ribotoxins, as the variants described here only presented small differences in terms of ribonucleolytic activity and cytotoxicity against cultured insect cells.

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