ArticleAntimicrobial agents and chemotherapy2017
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.
Article in Antimicrobial agents and chemotherapy, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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15 citing papers in PubMed, 21 citations in OpenAlex.
- Directed evolution of a beta-lactamase samples a wide variety of conformational states.Protein science : a publication of the Protein Society · 2025Article
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- Evolutionary Dynamics and Functional Differences in Clinically Relevant Pen β-Lactamases fromJournal of chemical information and modeling · 2025Article
- Diverse evolutionary trajectories ofmSystems · 2025Article
- Pulmonary microbial spectrum ofFrontiers in medicine · 2025Article
- Antimicrobial Susceptibility Profiles and Key Determinants for Mortality inInfectious diseases & clinical microbiology · 2023Article
- Insights into the Effects and Mechanism of Andrographolide-Mediated Recovery of Susceptibility of Methicillin-Resistant Staphylococcus aureus to β-Lactam Antibiotics.Microbiology spectrum · 2023Article
- Assessing the Potency of β-Lactamase Inhibitors with Diverse Inactivation Mechanisms against the PenA1 Carbapenemase fromACS infectious diseases · 2021Article
- Article
- Whole Genome Sequence Analysis of Burkholderia contaminans FFH2055 Strain Reveals the Presence of Putative β-Lactamases.Current microbiology · 2019Article
- Sequence heterogeneity of the PenA carbapenemase in clinical isolates of Burkholderia multivorans.Diagnostic microbiology and infectious disease · 2018Article
- Characterization of the AmpC β-Lactamase from Burkholderia multivorans.Antimicrobial agents and chemotherapy · 2018Article
- Successful Treatment of Persistent Burkholderia cepacia Complex Bacteremia with Ceftazidime-Avibactam.Antimicrobial agents and chemotherapy · 2018Article
- Therapies for multidrug resistant and extensively drug-resistant non-fermenting gram-negative bacteria causing nosocomial infections: a perilous journey toward 'molecularly targeted' therapy.Expert review of anti-infective therapy · 2018Review
- A 17-Year Nationwide Study of Burkholderia cepacia Complex Bloodstream Infections Among Patients in the United States Veterans Health Administration.Clinical infectious diseases : an official publication of the Infectious Diseases Society of America · 2017Article
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
Abstract
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. We found that up to 36% of 146 tested BCC clinical isolates were nonsusceptible to ceftazidime (MICs ≥ 8 μg/ml). To date, the biochemical basis for ceftazidime resistance in BCC is largely undefined. In this study, we investigated the role of the Ω-loop in mediating ceftazidime resistance in the PenA β-lactamase from Burkholderia multivorans, a species within the BCC. Single amino acid substitutions were engineered at selected positions (R164, T167, L169, and D179) in the PenA β-lactamase. Cell-based susceptibility testing revealed that 21 of 75 PenA variants engineered in this study were resistant to ceftazidime, with MICs of >8 μg/ml. Under steady-state conditions, each of the selected variants (R164S, T167G, L169A, and D179N) demonstrated a substrate preference for ceftazidime compared to wild-type PenA (32- to 320-fold difference). Notably, the L169A variant hydrolyzed ceftazidime significantly faster than PenA and possessed an ∼65-fold-lower apparent K
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