“Switching Partners”: Piperacillin-Avibactam Is a Highly Potent Combination against Multidrug-Resistant
            <i>Burkholderia cepacia</i>
            Complex and
            <i>Burkholderia gladioli</i>
            Cystic Fibrosis Isolates

Zeiser, Elise T.; Becka, Scott A.; Wilson, Brigid; Barnes, Melissa D.; LiPuma, John J.; Papp-Wallace, Krisztina M.

doi:10.1128/jcm.00181-19

Cited by 27 publications

(17 citation statements)

References 27 publications

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“…Rice isolates comprised B. gladioli BSR3, one of the most notable rice pathogenic Burkholderia species [ 21 , 63 , 64 , 65 ], and B. gladioli KACC 18962, which was isolated in this study, presenting similar phenotype traits with strain BSR3. Human isolates were composed of opportunistic human pathogenic and multidrug-resistant B. gladioli (AU0032, AU26456, AU29541 and AU30473) in which antibiotic susceptibility profiling has been recently undertaken [ 66 , 67 ]. In addition, B. gladioli , which were isolated from water and soil for industrial application [ 28 ], were included in nature isolates.…”

Section: Resultsmentioning

confidence: 99%

Pan-Genome Analysis Reveals Host-Specific Functional Divergences in Burkholderia gladioli

et al. 2021

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Burkholderia gladioli has high versatility and adaptability to various ecological niches. Here, we constructed a pan-genome using 14 genome sequences of B. gladioli, which originate from different niches, including gladiolus, rice, humans, and nature. Functional roles of core and niche-associated genomes were investigated by pathway enrichment analyses. Consequently, we inferred the uniquely important role of niche-associated genomes in (1) selenium availability during competition with gladiolus host; (2) aromatic compound degradation in seed-borne and crude oil-accumulated environments, and (3) stress-induced DNA repair system/recombination in the cystic fibrosis-niche. We also identified the conservation of the rhizomide biosynthetic gene cluster in all the B. gladioli strains and the concentrated distribution of this cluster in human isolates. It was confirmed the absence of complete CRISPR/Cas system in both plant and human pathogenic B. gladioli and the presence of the system in B. gladioli living in nature, possibly reflecting the inverse relationship between CRISPR/Cas system and virulence.

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Section: Resultsmentioning

confidence: 99%

Pan-Genome Analysis Reveals Host-Specific Functional Divergences in Burkholderia gladioli

et al. 2021

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“…CLSI breakpoints for piperacillin-tazobactam were based on those for Pseudomonas aeruginosa and breakpoints for ceftazidime-avibactam were based on those for ceftazidime for BCC. 31 No published studies have evaluated the clinical efficacy of the combination.…”

Section: Mechanisms Of Resistancementioning

confidence: 99%

An Overview of the Treatment of Less Common Non–Lactose‐Fermenting Gram‐Negative Bacteria

et al. 2020

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Stenotrophomonas maltophilia, Burkholderia cepacia complex, Elizabethkingia spp., Chryseobacterium spp., Achromobacter spp., and Alcaligenes spp. are less‐common non–lactose‐fermenting bacteria that have emerged as important opportunistic pathogens. Patients at the highest risk for these infections include the immunocompromised, those with cystic fibrosis, and the critically ill. These opportunistic pathogens are frequently drug resistant through the expression of β‐lactamases, multidrug efflux pumps, aminoglycoside‐modifying enzymes, and target site alterations discussed in detail throughout this review. As a result, treatment is extremely challenging. For each pathogen, this review will examine the epidemiology, mechanisms of resistance, and in vitro and in vivo data including that for novel β‐lactam/β‐lactamase inhibitors and cefiderocol. Treatment recommendations are provided based on the available literature.

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“…To evaluate the efficacy of the various β-lactamase inhibitors against PenA1, the bla PenA1 gene was cloned and expressed in Escherichia coli DH10B for susceptibility testing. Piperacillin was selected as the partner β-lactam, as previously piperacillin was found to be a potent partner against clinical isolates of Bcc . The newer β-lactamase inhibitors, avibactam, relebactam, enmetazobactam, and vaborbactam reduced piperacillin minimum inhibitory concentrations (MICs) to the susceptible range (MICs: 2–8 μg/mL) for E .…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2021

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Burkholderia cepacia 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. Avibactam was previously shown to be a potent inactivator of PenA1. Here, we examined the inactivation mechanism of PenA1, a class A serine carbapenemase from Burkholderia multivorans using β-lactamase inhibitors (β-lactam-, diazabicyclooctane-, and boronate-based) with diverse mechanisms of action. In whole cell based assays, avibactam, relebactam, enmetazobactam, and vaborbactam restored susceptibility to piperacillin against PenA1 expressed in Escherichia coli. The rank order of potency of inactivation in vitro based on k inact/K I or k 2/K values (range: 3.4 × 102 to 2 × 106 M–1 s–1) against PenA1 was avibactam > enmetazobactam > tazobactam > relebactam > clavulanic acid > vaborbactam. The contribution of selected amino acids (S70, K73, S130, E166, N170, R220, K234, T237, and D276) in PenA1 toward inactivation was evaluated using site-directed mutagenesis. The S130A, R220A, and K234A variants of PenA1 were less susceptible to inactivation by avibactam. The R220A variant was purified and assessed via steady-state inhibition kinetics and found to possess increased K i‑app values and decreased k inact/K I or k 2/K values against all tested inhibitors compared to PenA1. Avibactam was the most affected by the alanine replacement at 220 with a nearly 400-fold decreased acylation rate. The X-ray crystal structure of the R220A variant was solved and revealed loss of the hydrogen bonding network between residues 237 and 276 leaving a void in the active site that was occupied instead by water molecules. Michaelis–Menten complexes were generated to elucidate the molecular contributions of the poorer in vitro inhibition profile of vaborbactam against PenA1 (k 2/K, 3.4 × 102 M–1 s–1) and was compared to KPC-2, a class A carbapenemase that is robustly inhibited by vaborbactam. The active site of PenA1 is larger than that of KPC-2, which impacted the ability of vaborbactam to form favorable interactions, and as a result the carboxylate of vaborbactam was drawn toward K234/T235 in PenA1 displacing the boronic acid from approaching the nucleophilic S70. Moreover, in PenA1, the tyrosine at position 105 compared to tryptophan in KPC-2, was more flexible rotating more than 90°, and as a result PenA1’s Y105 competed for binding with the cyclic boronate vs the thiophene moiety of vaborbactam, further precluding inhibition of PenA1 by vaborbactam. Given the 400-fold decreased k 2/K for the R220A variant compared to PenA1, acyl–enzyme complexes were generated via molecular modeling and compared to the PenA1-avibactam crystal structure. The water molecules occupying the active site of the R220A variant are unable to stabilize the T237 and D276 region of the active site altering the ability of avibactam to form favo...

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“Switching Partners”: Piperacillin-Avibactam Is a Highly Potent Combination against Multidrug-Resistant Burkholderia cepacia Complex and Burkholderia gladioli Cystic Fibrosis Isolates

Cited by 27 publications

References 27 publications

Pan-Genome Analysis Reveals Host-Specific Functional Divergences in Burkholderia gladioli

Pan-Genome Analysis Reveals Host-Specific Functional Divergences in Burkholderia gladioli

An Overview of the Treatment of Less Common Non–Lactose‐Fermenting Gram‐Negative Bacteria

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

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