Frameshift Mutations in Genes Encoding PBP3 and PBP4 Trigger an Unusual, Extreme β-Lactam Resistance Phenotype in .

In our curated panel of complex isolates, strain AU28442 was unusually highly β-lactam resistant. To explore the molecular mechanisms leading to this phenotype, we performed whole genome sequencing (WGS) and microbiological and biochemical assays. WGS analysis revealed that strain AU28442 produced two β-lactamases, AmpC22 and a novel PenA-like β-lactamase denominated PenA39.

Cefepime-taniborbactam demonstrates potent activity vs with .

Taniborbactam (formerly VNRX-5133) is a novel, investigational boronic acid β-lactamase inhibitor. The combination of cefepime (FEP) with taniborbactam is active against carrying class A, B, C, and/or D enzymes. We assessed the activity of FEP-taniborbactam against clinical strains carrying ( = 50, 100%), of which 78% harbored at least one extended-spectrum β-lactamase (ESBL).

Examining the activity of cefepime-taniborbactam against complex and isolated from cystic fibrosis patients in the United States.

The novel clinical-stage β-lactam-β-lactamase inhibitor combination, cefepime-taniborbactam, demonstrates promising activity toward many Gram-negative bacteria producing class A, B, C, and/or D β-lactamases. We tested this combination against a panel of 150 complex (Bcc) and strains. The addition of taniborbactam to cefepime shifted cefepime minimum inhibitory concentrations toward the provisionally susceptible range in 59% of the isolates tested.

Activity of ETX0462 toward Some spp.

Burkholderia cepacia complex (Bcc) and Burkholderia gladioli are opportunistic human pathogens that are inherently multidrug resistant, limiting treatment options for infections. Here, a novel diazabicyclooctane, ETX0462, was evaluated for activity against Bcc and . .

The Class A β-Lactamase Produced by Species Compromises the Potency of Tebipenem against a Panel of Isolates from the United States.

Tebipenem-pivoxil hydrobromide, an orally bioavailable carbapenem, is currently in clinical development for the treatment of extended-spectrum β-lactamase- and AmpC-producing Enterobacterales. Previously, tebipenem was found to possess antimicrobial activity against the biothreat pathogens, and . Thus, herein, tebipenem was evaluated against a panel of 150 curated strains of complex (Bcc) and , pathogens that infect people who are immunocompromised or have cystic fibrosis.

Activity of Imipenem-Relebactam against Multidrug- and Extensively Drug-Resistant Burkholderia cepacia Complex and Burkholderia gladioli.

The Burkholderia cepacia complex (Bcc) and Burkholderia gladioli are opportunistic pathogens that most commonly infect persons with cystic fibrosis or compromised immune systems. Members of the genus are intrinsically multidrug resistant (MDR), possessing both a PenA carbapenemase and an AmpC β-lactamase, rendering treatment of infections due to these species problematic. Here, we tested the β-lactam-β-lactamase inhibitor combination imipenem-relebactam against a panel of MDR Bcc and B.

Assessing the Potency of β-Lactamase Inhibitors with Diverse Inactivation Mechanisms against the PenA1 Carbapenemase from .

complex (Bcc) poses a serious health threat to people with cystic fibrosis or compromised immune systems. Infections often arise from Bcc strains, which are highly resistant to many classes of antibiotics, including β-lactams. β-Lactam resistance in Bcc is conferred largely via PenA-like β-lactamases.

Structural Analysis of The OXA-48 Carbapenemase Bound to A "Poor" Carbapenem Substrate, Doripenem.

Carbapenem-resistant Enterobacteriaceae are a significant threat to public health, and a major resistance determinant that promotes this phenotype is the production of the OXA-48 carbapenemase. The activity of OXA-48 towards carbapenems is a puzzling phenotype as its hydrolytic activity against doripenem is non-detectable. To probe the mechanistic basis for this observation, we determined the 1.

"Switching Partners": Piperacillin-Avibactam Is a Highly Potent Combination against Multidrug-Resistant Complex and Cystic Fibrosis Isolates.

In persons with cystic fibrosis (CF), airway infection with complex (Bcc) species or presents a significant challenge due to inherent resistance to multiple antibiotics. Two chromosomally encoded inducible β-lactamases, a Pen-like class A and AmpC are produced in Bcc and Previously, ceftazidime-avibactam demonstrated significant potency against Bcc and isolated from the sputum of individuals with CF; however, 10% of the isolates tested resistant to ceftazidime-avibactam. Here, we describe an alternative antibiotic combination to overcome ceftazidime-avibactam resistance.

Ceftazidime-Avibactam in Combination With Fosfomycin: A Novel Therapeutic Strategy Against Multidrug-Resistant Pseudomonas aeruginosa.

Previously, by targeting penicillin-binding protein 3, Pseudomonas-derived cephalosporinase (PDC), and MurA with ceftazidime-avibactam-fosfomycin, antimicrobial susceptibility was restored among multidrug-resistant (MDR) Pseudomonas aeruginosa. Herein, ceftazidime-avibactam-fosfomycin combination therapy against MDR P. aeruginosa clinical isolate CL232 was further evaluated.

Resurrecting Old β-Lactams: Potent Inhibitory Activity of Temocillin against Multidrug-Resistant Species Isolates from the United States.

spp. are opportunistic human pathogens that infect persons with cystic fibrosis and the immunocompromised. spp.

Sequence heterogeneity of the PenA carbapenemase in clinical isolates of Burkholderia multivorans.

Multidrug-resistant gram-negative pathogens are a significant health threat. Burkholderia spp. encompass a complex subset of gram-negative bacteria with a wide range of biological functions that include human, animal, and plant pathogens.

Relebactam Is a Potent Inhibitor of the KPC-2 β-Lactamase and Restores Imipenem Susceptibility in KPC-Producing Enterobacteriaceae.

The imipenem-relebactam combination is in development as a potential treatment regimen for infections caused by possessing complex β-lactamase backgrounds. Relebactam is a β-lactamase inhibitor that possesses the diazabicyclooctane core, as in avibactam; however, the R1 side chain of relebactam also includes a piperidine ring, whereas that of avibactam is a carboxyamide. Here, we investigated the inactivation of the carbapenemase KPC-2, the most widespread class A carbapenemase, by relebactam and performed susceptibility testing with imipenem-relebactam using KPC-producing clinical isolates of MIC measurements using agar dilution methods revealed that all 101 clinical isolates of KPC-producing (, , , , , , and ) were highly susceptible to imipenem-relebactam (MICs ≤ 2 mg/liter).

Inactivation of the Pseudomonas-Derived Cephalosporinase-3 (PDC-3) by Relebactam.

is a prevalent and life-threatening Gram-negative pathogen. -derived cephlosporinase (PDC) is the major inducible cephalosporinase in In this investigation, we show that relebactam, a diazabicyclooctane β-lactamase inhibitor, potently inactivates PDC-3, with a / of 41,400 M s and a of 0.00095 s Relebactam restored susceptibility to imipenem in 62% of multidrug-resistant clinical isolates, while only 21% of isolates were susceptible to imipenem-cilastatin alone.

Overcoming an Extremely Drug Resistant (XDR) Pathogen: Avibactam Restores Susceptibility to Ceftazidime for Burkholderia cepacia Complex Isolates from Cystic Fibrosis Patients.

Burkholderia multivorans is a significant health threat to persons with cystic fibrosis (CF). Infections are difficult to treat as this pathogen is inherently resistant to multiple antibiotics. Susceptibility testing of isolates obtained from CF respiratory cultures revealed that single agents selected from different antibiotic classes were unable to inhibit growth.

Exposing a β-Lactamase "Twist": the Mechanistic Basis for the High Level of Ceftazidime Resistance in the C69F Variant of the Burkholderia pseudomallei PenI β-Lactamase.

Around the world, Burkholderia spp. are emerging as pathogens highly resistant to β-lactam antibiotics, especially ceftazidime. Clinical variants of Burkholderia pseudomallei possessing the class A β-lactamase PenI with substitutions at positions C69 and P167 are known to demonstrate ceftazidime resistance.

Characterization of the adhesive properties of the type IIb subfamily receptor protein tyrosine phosphatases.

Receptor protein tyrosine phosphatases (RPTPs) have cell adhesion molecule-like extracellular domains coupled to cytoplasmic tyrosine phosphatase domains. PTPmu is the prototypical member of the type IIb subfamily of RPTPs, which includes PTPrho, PTPkappa, and PCP-2. The authors performed the first comprehensive analysis of the subfamily in one system, examining adhesion and antibody recognition.

Cancer-derived mutations in the fibronectin III repeats of PTPRT/PTPrho inhibit cell-cell aggregation.

Abstract The receptor protein tyrosine phosphatase T PTPrho is the most frequently mutated tyrosine phosphatase in human cancer. PTPrho mediates homophilic cell-cell aggregation. In its extracellular region, PTPrho has cell adhesion molecule-like motifs, including a MAM domain, an immunoglobulin domain, and four fibronectin type III (FNIII) repeats.

Tumor-derived extracellular mutations of PTPRT /PTPrho are defective in cell adhesion.

Receptor protein tyrosine phosphatase T (PTPRT/PTPrho) is frequently mutated in human cancers including colon, lung, gastric, and skin cancers. More than half of the identified tumor-derived mutations are located in the extracellular part of PTPrho. However, the functional significance of those extracellular domain mutations remains to be defined.