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.

The Effectiveness of Imipenem-Relebactam against Ceftazidime-Avibactam Resistant Variants of the KPC-2 β-Lactamase.

Background: Ceftazidime-avibactam was approved by the FDA to treat infections caused by Enterobacterales carrying . However, variants of KPC-2 with amino acid substitutions at position 179 have emerged and confer resistance to ceftazidime-avibactam.

Methods: The activity of imipenem-relebactam was assessed against a panel of 19 KPC-2 D179 variants.

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.

Probing the Mechanism of Inactivation of the FOX-4 Cephamycinase by Avibactam.

Ceftazidime-avibactam is a "second-generation" β-lactam-β-lactamase inhibitor combination that is effective against 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.

Exploring the Landscape of Diazabicyclooctane (DBO) Inhibition: Avibactam Inactivation of PER-2 β-Lactamase.

PER β-lactamases are an emerging family of extended-spectrum β-lactamases (ESBL) found in Gram-negative bacteria. PER β-lactamases are unique among class A enzymes as they possess an inverted omega (Ω) loop and extended B3 β-strand. These singular structural features are hypothesized to contribute to their hydrolytic profile against oxyimino-cephalosporins (e.

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.

Exploring the Role of the Ω-Loop in the Evolution of Ceftazidime Resistance in the PenA β-Lactamase from Burkholderia multivorans, an Important Cystic Fibrosis Pathogen.

The unwelcome evolution of resistance to the advanced generation cephalosporin antibiotic, ceftazidime is hindering the effective therapy of Burkholderia cepacia complex (BCC) infections. Regrettably, BCC organisms are highly resistant to most antibiotics, including polymyxins; ceftazidime and trimethoprim-sulfamethoxazole are the most effective treatment options. Unfortunately, resistance to ceftazidime is increasing and posing a health threat to populations susceptible to BCC infection.