is a clinically important, Gram-negative pathogen responsible for a wide variety of nosocomial and community-acquired infections. Antibiotic resistance is a serious concern, as the organism has a wide variety of intrinsic resistance mechanisms, including chromosomal class C () and D ( family) β-lactamases, and the ability to readily acquire additional β-lactamases. Surveillance studies can reveal the diversity and distribution of β-lactamase alleles, but are difficult and expensive to conduct.
View Article and Find Full Text PDFis a clinically important Gram-negative pathogen responsible for a wide variety of serious nosocomial and community-acquired infections. Antibiotic resistance is a major concern, as this organism has a wide variety of resistance mechanisms, including chromosomal class C () and D ( family) β-lactamases, efflux pumps, porin channels, and the ability to readily acquire additional β-lactamases. Surveillance studies can reveal the diversity and distribution of β-lactamase alleles but are difficult and expensive to conduct.
View Article and Find Full Text PDFLedaborbactam (formerly VNRX-5236), a bicyclic boronate β-lactamase inhibitor with activity against class A, C, and D β-lactamases, is under development as an orally bioavailable etzadroxil prodrug (VNRX-7145) in combination with ceftibuten for the treatment of urinary tract infections. At ceftibuten breakpoints of ≤1 mg/L (EUCAST) and ≤8 mg/L (CLSI), 92.5% and 99.
View Article and Find Full Text PDFTaniborbactam, a bicyclic boronate β-lactamase inhibitor with activity against carbapenemase (KPC), Verona integron-encoded metallo-β-lactamase (VIM), New Delhi metallo-β-lactamase (NDM), extended-spectrum beta-lactamases (ESBLs), OXA-48, and AmpC β-lactamases, is under clinical development in combination with cefepime. Susceptibility of 200 previously characterized carbapenem-resistant and 197 multidrug-resistant (MDR) to cefepime-taniborbactam and comparators was determined by broth microdilution. For (192 KPC; 7 OXA-48-related), MIC values of β-lactam components for cefepime-taniborbactam, ceftazidime-avibactam, and meropenem-vaborbactam were 2, 2, and 1 mg/L, respectively.
View Article and Find Full Text PDFJ Am Acad Orthop Surg Glob Res Rev
April 2024
Background: Little is known about the effect of surgical approach on return to braking after total hip arthroplasty (THA), and few studies have investigated braking after THA with modern surgical techniques and rehabilitation protocols.
Methods: In a prospective comparative design, we enrolled 65 patients who received right-sided primary THA at our institution from April 2018 through March 2020, 34 with a direct anterior approach (DAA) and 31 with a posterior approach (PA). Braking tests measuring brake reaction time (BRT) and brake pedal depression (BPD) were administered to patients preoperatively and at 1, 2, and 4 weeks postoperatively using a realistic driving simulator.
The expression of antibiotic-inactivating enzymes, such as -derived cephalosporinase-3 (PDC-3), is a major mechanism of intrinsic resistance in bacteria. To explore the relationships between structural dynamics and altered substrate specificity as a result of amino acid substitutions in PDC-3, innovative computational methods like machine learning driven adaptive bandit molecular dynamics simulations and markov state modeling of the wild-type PDC-3 and nine clinically identified variants were conducted. Our analysis reveals that structural changes in the Ω loop controls the dynamics of the active site.
View Article and Find Full Text PDFCompared to other genera of Gram-negative pathogens, is adept in acquiring complex non-enzymatic and enzymatic resistance mechanisms thus remaining a challenge to even novel antibiotics including recently developed β-lactam and β-lactamase inhibitor combinations. This study shows that the novel β-lactam enhancer approach enables cefepime/zidebactam to overcome both non-enzymatic and enzymatic resistance mechanisms associated with a challenging panel of . This study highlights that the β-lactam enhancer mechanism is a promising alternative to the conventional β-lactam/β-lactamase inhibitor approach in combating ever-evolving MDR .
View Article and Find Full Text PDFA wide variety of clinically observed single amino acid substitutions in the Ω-loop region have been associated with increased minimum inhibitory concentrations and resistance to ceftazidime (CAZ) and ceftolozane (TOL) in -derived cephalosporinase and other class C β-lactamases. Herein, we demonstrate the naturally occurring tyrosine to histidine substitution of amino acid 221 (Y221H) in -derived cephalosporinase (PDC) enables CAZ and TOL hydrolysis, leading to similar kinetic profiles ( = 2.3 ± 0.
View Article and Find Full Text PDFThe RNA-dependent RNA polymerase of the severe acute respiratory syndrome coronavirus 2 virus is error prone, with errors being corrected by the exonuclease (NSP14) proofreading mechanism. However, the mutagenesis and subsequent evolutionary trajectory of the virus is mediated by the delicate interplay of replicase fidelity and environmental pressures. Here, we have shown that a single, distal mutation (F60S) in NSP14 can have a profound impact upon proofreading with an increased accumulation of mutations and elevated evolutionary rate being observed.
View Article and Find Full Text PDFThe integrins and G protein-coupled receptors are both fundamental in cell biology. The cross talk between these two, however, is unclear. Here we show that β integrins negatively regulate G protein-coupled signaling by directly inhibiting the Gα-p115RhoGEF interaction.
View Article and Find Full Text PDFAntimicrob Agents Chemother
May 2022
Multidrug-resistant (MDR) Pseudomonas aeruginosa infections are a major clinical challenge. Many isolates are carbapenem resistant, which severely limits treatment options; thus, novel therapeutic combinations, such as imipenem-relebactam (IMI/REL), ceftazidime-avibactam (CAZ/AVI), ceftolozane-tazobactam (TOL/TAZO), and meropenem-vaborbactam (MEM/VAB) were developed. Here, we studied two extensively drug-resistant (XDR) P.
View Article and Find Full Text PDFHow early human foragers impacted insular forests is a topic with implications across multiple disciplines, including resource management. Paradoxically, terminal Pleistocene and Early Holocene impacts of foraging communities have been characterized as both extreme-as in debates over human-driven faunal extinctions-and minimal compared to later landscape transformations by farmers and herders. We investigated how rainforest hunter-gatherers managed resources in montane New Guinea and present some of the earliest documentation of Late Pleistocene through mid-Holocene exploitation of cassowaries (Aves: Casuariidae).
View Article and Find Full Text PDFUnderstanding allostery in enzymes and tools to identify it offer promising alternative strategies to inhibitor development. Through a combination of equilibrium and nonequilibrium molecular dynamics simulations, we identify allosteric effects and communication pathways in two prototypical class A β-lactamases, TEM-1 and KPC-2, which are important determinants of antibiotic resistance. The nonequilibrium simulations reveal pathways of communication operating over distances of 30 Å or more.
View Article and Find Full Text PDFSuccessful treatment of Acinetobacter baumannii infections require early and appropriate antimicrobial therapy. One of the first steps in this process is understanding which β-lactamase (bla) alleles are present and in what combinations. Thus, we performed WGS on 98 carbapenem-resistant A.
View Article and Find Full Text PDFInfect Dis Clin North Am
December 2020
Significant advances were made in antibiotic development during the past 5 years. Novel agents were added to the arsenal that target critical priority pathogens, including multidrug-resistant Pseudomonas aeruginosa and carbapenem-resistant Enterobacterales. Of these, 4 novel β-lactam-β-lactamase inhibitor combinations (ceftolozane-tazobactam, ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-cilastatin-relebactam) reached clinical approval in the United States.
View Article and Find Full Text PDFHow predictable are life trajectories? We investigated this question with a scientific mass collaboration using the common task method; 160 teams built predictive models for six life outcomes using data from the Fragile Families and Child Wellbeing Study, a high-quality birth cohort study. Despite using a rich dataset and applying machine-learning methods optimized for prediction, the best predictions were not very accurate and were only slightly better than those from a simple benchmark model. Within each outcome, prediction error was strongly associated with the family being predicted and weakly associated with the technique used to generate the prediction.
View Article and Find Full Text PDFUnlike for classes A and B, a standardized amino acid numbering scheme has not been proposed for the class C (AmpC) β-lactamases, which complicates communication in the field. Here, we propose a scheme developed through a collaborative approach that considers both sequence and structure, preserves traditional numbering of catalytically important residues (Ser, Lys, Tyr, and Lys), is adaptable to new variants or enzymes yet to be discovered and includes a variation for genetic and epidemiological applications.
View Article and Find Full Text PDFAvian diversification has been influenced by global climate change, plate tectonic movements, and mass extinction events. However, the impact of these factors on the diversification of the hyperdiverse perching birds (passerines) is unclear because family level relationships are unresolved and the timing of splitting events among lineages is uncertain. We analyzed DNA data from 4,060 nuclear loci and 137 passerine families using concatenation and coalescent approaches to infer a comprehensive phylogenetic hypothesis that clarifies relationships among all passerine families.
View Article and Find Full Text PDFThe matrix (MA) domain of the HIV-1 precursor Gag protein (PrGag) has been shown interact with the HIV-1 envelope (Env) protein, and to direct PrGag proteins to plasma membrane (PM) assembly sites by virtue of its affinity to phosphatidylinositol-4,5-bisphosphate (PI[4,5]P2). Unexpectedly, HIV-1 viruses with large MA deletions (ΔMA) have been shown to be conditionally infectious as long as they are matched with Env truncation mutant proteins or alternative viral glycoproteins. To characterize the interactions of wild type (WT) and ΔMA Gag proteins with PI(4,5)P2 and other acidic phospholipids, we have employed a set of lipid biosensors as probes.
View Article and Find Full Text PDFUnlabelled: The purpose of this study was to update the results of a prospective series of 100 primary cementless total hip arthroplasty (THA) procedures that were performed between 1983 and 1986 with use of the Porous Coated Anatomic (PCA) system. This is one of the first prospective studies of cementless primary THA with a minimum of 25 years of follow-up. Twenty-one patients (22 hips) of the original series were alive and had clinical and radiographic follow-up at a minimum of 25 years postoperatively.
View Article and Find Full Text PDFBackground: Mutations of the human K-Ras 4B (K-Ras) G protein are associated with a significant proportion of all human cancers. Despite this fact, a comprehensive analysis of K-Ras interactions is lacking. Our investigations focus on characterization of the K-Ras interaction network.
View Article and Find Full Text PDFBackground: Total joint arthroplasty (TJA) is one of the most successful operations. There is little in the literature regarding weight change following TJA, particularly in a young cohort.
Methods: Retrospective analysis of 181 primary total hip arthroplasty (THA) and 185 primary total knee arthroplasty (TKA) patients was conducted.