Resurrecting Old β-Lactams: Potent Inhibitory Activity of Temocillin against Multidrug-Resistant<i>Burkholderia</i>Species Isolates from the United States

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

doi:10.1128/aac.02315-18

Cited by 10 publications

(11 citation statements)

References 49 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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“…The marked β-lactam susceptibility of knockdown mutants in bla PenB , together with the ability of avibactam to inhibit PenA-family β-lactamases in Burkholderia species (Zeiser et al 2019), made us curious about the broader applicability of AVI/AZT and AVI/MEM combinations. AVI/AZT and AVI/MEM are not commonly used to treat Bcc respiratory infection.…”

Section: Resultsmentioning

confidence: 99%

“…lactams. Our findings also demonstrate that BarSeq can be used to elucidate the mechanisms and targets of antibiotic potentiation.The marked β-lactam susceptibility of knockdown mutants in blaPenB, together with the ability of avibactam to inhibit PenA-family β-lactamases in Burkholderia species[68], suggested a broader applicability of AVI/AZT and AVI/MEM combinations. Thus, we assembled a panel of 41 clinical Bcc isolates (including B. gladioli) spanning the last two decades and representing the most commonly recovered species across Canada.…”

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confidence: 99%

Profiling cell envelope-antibiotic interactions reveals vulnerabilities to β-lactams in a multidrug-resistant bacterium

Hogan

Maydaniuk

Natarajan

et al. 2022

Preprint

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The cell envelope of the Gram-negativeBurkholderia cepaciacomplex (Bcc) presents unique restrictions to antibiotic penetration. As a consequence, Bcc species are notorious for causing recalcitrant multidrug-resistant infections in immunocompromised individuals, such as those living with cystic fibrosis. To systematically identify cell envelope-associated resistance and susceptibility determinants at the genome level, we constructed a high-density, randomly-barcoded transposon mutant library in the clinical isolateB. cenocepaciaK56-2 and exposed it to a panel of more than twenty cell envelope-targeting antibiotics. By quantifying relative mutant fitness with BarSeq, followed by validation with CRISPR-interference, we profiled over a hundred new chemical-genetic interactions and identified novel mediators of antibiotic susceptibility in the Bcc cell envelope. We first reveal new connections between broad-spectrum β-lactam susceptibility, peptidoglycan synthesis, and blockages in undecaprenyl phosphate metabolism, highlighting a β-lactam critical vulnerability associated with sharing this common lipid intermediate. We then show that the clinically relevant synergy of the β-lactam/ β-lactamase inhibitor combination ceftazidime/avibactam is primarily mediated by inhibition of the PenB carbapenemase, over more than twenty other putative β-lactamases. Importantly, avibactam more strongly potentiates the activity of aztreonam and meropenem than ceftazidime in a panel of Bcc clinical isolates. Finally, we characterize for first time in the Bcc the iron and receptor-dependent activity of the novel siderophore cephalosporin antibiotic, cefiderocol. Overall, our work has implications for antibiotic target prioritization, and for using additional combinations of β-lactam/ β-lactamase inhibitors that can extend the utility of our current clinical arsenal of antibacterial therapies.

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“…The Burkholderia sp. (i.e., Bcc and B. gladioli) clinical isolates used in this study were obtained from the Burkholderia cepacia Research Laboratory and Repository strain collection, as previously described (8,23). The construction of strains that were used for susceptibly testing, as well as protein expression, was previously described (16,18).…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2019

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In persons with cystic fibrosis (CF), airway infection with Burkholderia cepacia complex (Bcc) species or Burkholderia gladioli presents a significant challenge due to inherent resistance to multiple antibiotics. Two chromosomally encoded inducible ␤-lactamases, a Pen-like class A and AmpC are produced in Bcc and B. gladioli. Previously, ceftazidime-avibactam demonstrated significant potency against Bcc and B. gladioli 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. Antimicrobial susceptibility testing was performed on Bcc and B. gladioli clinical and control isolates. Biochemical analysis was conducted on purified PenA1 and AmpC1 ␤-lactamases from Burkholderia multivorans ATCC 17616. Analytic isoelectric focusing and immunoblotting were conducted on cellular extracts of B. multivorans induced by various ␤-lactams or ␤-lactam-␤-lactamase inhibitor combinations. Combinations of piperacillin-avibactam, as well as piperacillin-tazobactam plus ceftazidime-avibactam (the clinically available counterpart), were tested against a panel of ceftazidime-avibactam nonsusceptible Bcc and B. gladioli. The piperacillin-avibactam and piperacillin-tazobactam-ceftazidime-avibactam combinations restored susceptibility to 99% of the isolates tested. Avibactam is a potent inhibitor of PenA1 (apparent inhibitory constant [K i app ] ϭ 0.5 M), while piperacillin was found to inhibit AmpC1 (K i app ϭ 2.6 M). Moreover, piperacillin, tazobactam, ceftazidime, and avibactam, as well as combinations thereof, did not induce expression of bla penA1 and bla ampC1 in the B. multivorans ATCC 17616 background. When ceftazidime-avibactam is combined with piperacillin-tazobactam, the susceptibility of Bcc and B. gladioli to ceftazidime and piperacillin is restored in vitro. Both the lack of bla penA1 induction and potent inactivation of PenA1 by avibactam likely provide the major contributions toward susceptibility. With in vivo validation, piperacillin-tazobactamceftazidime-avibactam may represent salvage therapy for individuals with CF and highly drug-resistant Bcc and B. gladioli infections.

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

Cited by 10 publications

References 49 publications

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

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

Profiling cell envelope-antibiotic interactions reveals vulnerabilities to β-lactams in a multidrug-resistant bacterium

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

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