Characterization of a novel Zn2+-dependent intrinsic imipenemase from Pseudomonas aeruginosa

Fajardo, Alicia; Hernando-Amado, Sara; Oliver, Antonio; Ball, Geneviève; Filloux, Alain; Martínez, José Luis

doi:10.1093/jac/dku267

Cited by 29 publications

(33 citation statements)

References 39 publications

(32 reference statements)

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“…P. aeruginosa clinical isolates often harbor acquired ␤-lactamases, particularly those of the oxacillinase type (class D) and the metallo-␤-lactamase IMP and VIM types (class B) (23,25,(53)(54)(55)(56)(57)(58). Chromosomally, P. aeruginosa carries a cephalosporinase, AmpC, that provides intrinsic resistance and that can be expressed at high levels in the presence of ␤-lactams (24, 59, 60) and a carbapenemase, PIB-1, that is reported to be ubiquitous but expressed at low levels in strain PAO1 (26). The aim of this study was to examine the role of a third chromosomally encoded class D ␤-lactamase, PoxB (OXA-50), in P. aeruginosa PAO1.…”

Section: Resultsmentioning

confidence: 99%

“…Mutational overexpression of PoxB has not been previously reported, but the introduction and use of the newly developed class A/C enzyme inhibitors, such as avibactam and relebactam, are likely to act as selective pressure for expression of the naturally encoding carbapenemases in P. aeruginosa, namely, PoxB (OXA-50) and the recently reported metallo-␤-lactamase PIB-1 (26). Relebactam, currently in clinical development in conjunction with imipenem-cilastatin, and its closely related counterpart, avibactam, can both inactivate P. aeruginosa AmpC but generally do not improve the activity of ␤-lactams against most class B and D enzymes (87,93,(101)(102)(103)(104).…”

Section: Figmentioning

confidence: 99%

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Characterization of a Carbapenem-Hydrolyzing Enzyme, PoxB, in Pseudomonas aeruginosa PAO1

Zincke

Balasubramanian

Silver³

et al. 2016

Antimicrob Agents Chemother

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cPseudomonas aeruginosa is an opportunistic pathogen often associated with severe and life-threatening infections that are highly impervious to treatment. This microbe readily exhibits intrinsic and acquired resistance to varied antimicrobial drugs. Resistance to penicillin-like compounds is commonplace and provided by the chromosomal AmpC ␤-lactamase. A second, chromosomally encoded ␤-lactamase, PoxB, has previously been reported in P. aeruginosa. In the present work, the contribution of this class D enzyme was investigated using a series of clean in-frame ampC, poxB, and oprD deletions, as well as complementation by expression under the control of an inducible promoter. While poxB deletions failed to alter ␤-lactam sensitivities, expression of poxB in ampC-deficient backgrounds decreased susceptibility to both meropenem and doripenem but had no effect on imipenem, penicillin, and cephalosporin MICs. However, when expressed in an ampCpoxB-deficient background, that additionally lacked the outer membrane porin-encoding gene oprD, PoxB significantly increased the imipenem as well as the meropenem and doripenem MICs. Like other class D carbapenem-hydrolyzing ␤-lactamases, PoxB was only poorly inhibited by class A enzyme inhibitors, but a novel non-␤-lactam compound, avibactam, was a slightly better inhibitor of PoxB activity. In vitro susceptibility testing with a clinical concentration of avibactam, however, failed to reduce PoxB activity against the carbapenems. In addition, poxB was found to be cotranscribed with an upstream open reading frame, poxA, which itself was shown to encode a 32-kDa protein of yet unknown function.

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Section: Resultsmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

Characterization of a Carbapenem-Hydrolyzing Enzyme, PoxB, in Pseudomonas aeruginosa PAO1

Zincke

Balasubramanian

Silver³

et al. 2016

Antimicrob Agents Chemother

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“…Several other ESBLs or MBLs have been reported in PA including oxacillin (OXA) class D ESBL [308][309][310] ; SHV-type ESBL in France 311 ; Thailand 312 ; Tunisia 313 ; Japan 314 ; Greece 315 ; AIM MBL (Australia) 316 ; TEM ESBLs [317][318][319] ; and PIB-1 (France). 229…”

Section: Other Esbls and Mblsmentioning

confidence: 99%

Emergence of Antimicrobial Resistance among Pseudomonas aeruginosa: Implications for Therapy

Lynch

Zhanel

Clark

2017

Semin Respir Crit Care Med

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Pseudomonas aeruginosa (PA), a nonlactose fermenting gram-negative bacillus, is a common cause of nosocomial infections in critically ill or debilitated patients, particularly ventilator-associated pneumonia (VAP), and infections of bloodstream, urinary tract, intra-abdominal, wounds/skin/soft tissue. PA rarely affects healthy individuals, but may cause serious infections in patients with chronic structural lung disease, comorbidities, advanced age, impaired immune defenses, or with medical devices (e.g., urinary or intravascular catheters, foreign bodies). Treatment of pseudomonal infections is difficult, as PA is intrinsically resistant to multiple antimicrobials, and may acquire new resistance determinants even while on antimicrobial therapy. Mortality associated with pseudomonal VAP or bacteremias is high (> 35%) and optimal therapy is controversial. Over the past three decades, antimicrobial resistance among PA has escalated globally, via dissemination of several international multidrug-resistant “epidemic” clones. We review the emergence of antimicrobial resistance to this pathogen, and discuss approaches to therapy (both empirical and definitive).

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“…Thus, znuA mutants show: reduced resistance to calprotectin inhibition; decreased secretion of extracellular zinccontaining proteases (LasA, LasB and Protease IV); and lower ability to produce alginate, which is required for the formation of biofilm. Moreover, intracellular variations in zinc concentration could have an impact on the resistance to β-lactam antibiotics that involves the expression of enzymes involving Zn(II) ions as essential factors or involves modulation in the expression of the porin OprD, a protein known to regulate resistance to carbapenems [43,44]. Taken together, these observations suggest that the search for compounds capable of blocking the import of zinc mediated by ZnuABC or other high-affinity metal transporters is a promising strategy to find new weapons to combat microbial infections.…”

Section: Executive Summarymentioning

confidence: 99%

A Novel Antimicrobial Approach Based on the Inhibition of Zinc Uptake in Salmonella Enterica

Battistoni

Ammendola

Chiancone³

et al. 2017

Future Med. Chem.

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In this review we discuss evidences suggesting that bacterial zinc homeostasis represents a promising target for new antimicrobial strategies. The ability of the gut pathogen Salmonella enterica sv Typhimurium to withstand the host responses aimed at controlling growth of the pathogen critically depends on the zinc importer ZnuABC. Strains lacking a functional ZnuABC or its soluble component ZnuA display a dramatic loss of pathogenicity, due to a reduced ability to express virulence factors; withstand the inflammatory response; and compete with other gut microbes. Based on this data, ZnuA was chosen as a candidate for the rational design of novel antibiotics. Through a combination of structural and functional investigations, we have provided a proof of concept of the potential of this approach.

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Characterization of a novel Zn2+-dependent intrinsic imipenemase from Pseudomonas aeruginosa

Cited by 29 publications

References 39 publications

Characterization of a Carbapenem-Hydrolyzing Enzyme, PoxB, in Pseudomonas aeruginosa PAO1

Characterization of a Carbapenem-Hydrolyzing Enzyme, PoxB, in Pseudomonas aeruginosa PAO1

Emergence of Antimicrobial Resistance among Pseudomonas aeruginosa: Implications for Therapy

A Novel Antimicrobial Approach Based on the Inhibition of Zinc Uptake in Salmonella Enterica

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