scholarly journals Mutation-driven evolution of Pseudomonas aeruginosa in the presence of either ceftazidime or ceftazidime/avibactam

2018 ◽  
Author(s):  
Fernando Sanz-García ◽  
Sara Hernando-Amado ◽  
José Luis Martínez
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Efflux Pump ◽  
Multidrug Resistant ◽  
Beta Lactam ◽  
Two Component System ◽  
Aminoglycoside Resistance ◽  
Beta Lactamases ◽  
Chromosomal Deletions ◽  
Main Driver ◽  
Selection Of

ABSTRACTCeftazidime/avibactam is a combination of beta-lactam/beta-lactamases inhibitor, which use is restricted to some clinical cases including cystic fibrosis patients infected with multidrug resistant Pseudomonas aeruginosa, in which mutation is the main driver of resistance. This study aims to predict the mechanisms of mutation-driven resistance that are selected for when P. aeruginosa is challenged with either ceftazidime or ceftazidime/avibactam. For this purpose, P. aeruginosa PA14 was submitted to experimental evolution in the absence of antibiotics and in the presence of increasing concentrations of ceftazidime or ceftazidime/avibactam for 30 consecutive days. Final populations were analysed by whole-genome sequencing. All evolved populations reached similar levels of ceftazidime resistance. Besides, all of them were more susceptible to amikacin and produced pyomelanin. A first event in the evolution was the selection of large chromosomal deletions containing hmgA (involved in pyomelanin production), galU (involved in β-lactams resistance) and mexXY-oprM (involved in aminoglycoside resistance). Besides mutations in mpl and dacB that regulate β-lactamase expression, mutations related to MexAB-OprM overexpression were prevalent. Ceftazidime/avibactam challenge selected mutants in the putative efflux pump PA14_45890-45910 and in a two-component system (PA14_45870-45880), likely regulating its expression. All populations produce pyomelanin and were more susceptible to aminoglycosides likely due to the selection of large chromosomal deletions. Since pyomelanin-producing mutants, presenting similar deletions are regularly isolated from infections, the potential aminoglycosides hyper-susceptiblity and reduced β-lactams susceptibility of pyomelanin-producing P. aeruginosa should be taken into consideration for treating infections by these isolates.

scholarly journals Mutation-Driven Evolution ofPseudomonas aeruginosain the Presence of either Ceftazidime or Ceftazidime-Avibactam

2018 ◽  
Vol 62 (10) ◽  
Author(s):  
Fernando Sanz-García ◽  
Sara Hernando-Amado ◽  
José Luis Martínez
Keyword(s):  
Experimental Evolution ◽  
Efflux Pump ◽  
Multidrug Resistant ◽  
Two Component System ◽  
Aminoglycoside Resistance ◽  
Content Type ◽  
Chromosomal Deletions ◽  
Two Component ◽  
Main Driver ◽  
Selection Of

ABSTRACTCeftazidime-avibactam is a combination of β-lactam/β-lactamase inhibitor, the use of which is restricted to some clinical cases, including cystic fibrosis patients infected with multidrug-resistantPseudomonas aeruginosa, in which mutation is the main driver of resistance. This study aims to predict the mechanisms of mutation-driven resistance that are selected for whenP. aeruginosais challenged with either ceftazidime or ceftazidime-avibactam. For this purpose,P. aeruginosaPA14 was submitted to experimental evolution in the absence of antibiotics and in the presence of increasing concentrations of ceftazidime or ceftazidime-avibactam for 30 consecutive days. Final populations were analyzed by whole-genome sequencing. All evolved populations reached similar levels of ceftazidime resistance. In addition, they were more susceptible to amikacin and produced pyomelanin. A first event in this evolution was the selection of large chromosomal deletions containinghmgA(involved in pyomelanin production),galU(involved in β-lactams resistance), andmexXY-oprM(involved in aminoglycoside resistance). Besides mutations inmplanddacBthat regulate β-lactamase expression, mutations related to MexAB-OprM overexpression were prevalent. Ceftazidime-avibactam challenge selected mutants in the putative efflux pumpPA14_45890andPA14_45910and in a two-component system (PA14_45870andPA14_45880), likely regulating its expression. All populations produced pyomelanin and were more susceptible to aminoglycosides, likely due to the selection of large chromosomal deletions. Since pyomelanin-producing mutants presenting similar deletions are regularly isolated from infections, the potential aminoglycoside hypersusceptiblity and reduced β-lactam susceptibility of pyomelanin-producingP. aeruginosashould be taken into consideration for treating infections caused by these isolates.

scholarly journals Expression of the MexXY Aminoglycoside Efflux Pump and Presence of an Aminoglycoside-Modifying Enzyme in Clinical Pseudomonas aeruginosa Isolates Are Highly Correlated

2020 ◽  
Vol 65 (1) ◽  
pp. e01166-20
Author(s):  
Alexander Seupt ◽  
Monika Schniederjans ◽  
Jürgen Tomasch ◽  
Susanne Häussler
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Efflux Pump ◽  
Aminoglycoside Resistance ◽  
Content Type ◽  
Main Driver ◽  
Gentamicin Resistance ◽  
Bacterial Cell Membrane ◽  
Highly Correlated ◽  
The Impact ◽  
Gene Expression Levels

ABSTRACTThe impact of MexXY efflux pump expression on aminoglycoside resistance in clinical Pseudomonas aeruginosa isolates has been debated. In this study, we found that, in general, elevated mexXY gene expression levels in clinical P. aeruginosa isolates confer to slight increases in aminoglycoside MIC levels; however, those levels rarely lead to clinically relevant resistance phenotypes. The main driver of resistance in the clinical isolates studied here was the acquisition of aminoglycoside-modifying enzymes (AMEs). Nevertheless, acquisition of an AME was strongly associated with mexY overexpression. In line with this observation, we demonstrate that the introduction of a gentamicin acetyltransferase confers to full gentamicin resistance levels in a P. aeruginosa type strain only if the MexXY efflux pump was active. We discuss that increased mexXY activity in clinical AME-harboring P. aeruginosa isolates might affect ion fluxes at the bacterial cell membrane and thus might play a role in the establishment of enhanced fitness that extends beyond aminoglycoside resistance.

scholarly journals MexXY efflux pump overexpression and aminoglycoside resistance in cystic fibrosis isolates of Pseudomonas aeruginosa from chronic infections

2017 ◽  
Vol 63 (12) ◽  
pp. 929-938 ◽  
Author(s):  
Manu Singh ◽  
Yvonne C.W. Yau ◽  
Shirley Wang ◽  
Valerie Waters ◽  
Ayush Kumar
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Efflux Pump ◽  
Multidrug Resistant ◽  
Regulatory Genes ◽  
Multidrug Efflux ◽  
Chronic Infections ◽  
Aminoglycoside Resistance ◽  
Resistance Nodulation Division ◽  
Lung Infections

In this study, we analyzed 15 multidrug-resistant cystic fibrosis isolates of Pseudomonas aeruginosa from chronic lung infections for expression of 4 different multidrug efflux systems (MexAB–OprM, MexCD–OprJ, MexEF–OprN, and MexXY), using quantitative reverse transcriptase PCR. Overexpression of MexXY pump was observed in all of the isolates tested. Analysis of regulatory genes that control the expression of these 4 efflux pumps revealed a number of previously uncharacterized mutations. Our work shows that MexXY pump overexpression is common in cystic fibrosis isolates and could be contributing to their reduced aminoglycoside susceptibility. Further, we also identified novel mutations in the regulatory genes of the 4 abovementioned Resistance–Nodulation–Division superfamily pumps that may be involved in the overexpression of these pumps.

Cocktail of CuO, ZnO, or CuZn Nanoparticles and Antibiotics for Combating Multidrug-Resistant Pseudomonas aeruginosa via Efflux Pump Inhibition

2021 ◽  
Vol 4 (9) ◽  
pp. 9799-9810
Author(s):  
Ioanna Eleftheriadou ◽  
Kleoniki Giannousi ◽  
Efthymia Protonotariou ◽  
Lemonia Skoura ◽  
Minas Arsenakis ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Efflux Pump ◽  
Multidrug Resistant ◽  
Efflux Pump Inhibition

scholarly journals Curcumin as Efflux Pump Inhibitor Agent for Enhancement Treatment Against Multidrug Resistant Pseudomonas aeruginosa Isolates

2020 ◽  
pp. 59-67
Author(s):  
Sulaiman D. Sulaiman ◽  
Ghusoon A. Abdulhasan
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Inhibitory Concentration ◽  
Efflux Pump ◽  
Multidrug Resistant ◽  
Diffusion Method ◽  
Disc Diffusion Method ◽  
Efflux Pump Inhibitor ◽  
Before And After ◽  
Chromogenic Agar ◽  
Susceptibility Patterns

  Pseudomonas aeruginosa is considered as a developing opportunistic nosocomial pathogen and is well-known for its multidrug resistance that can be efficiently treated by a combination of antibiotics andefflux pump inhibitors (EPI). Therefore, the purpose of this study was to investigate the effect of curcumin as an EPI for the enhancement of the effectiveness of antibiotics against multidrug resistant (MDR) isolates ofP. aeruginosa. Susceptibility patterns of suspected bacteria was determined using the disc diffusion method andresistant bacteria were identified using chromogenic agar and 16S rDNA. The effectsof curcuminon the enhancement of antibiotics’s activity was evaluated usingthe broth microdilution method.The susceptibility patterns for 50 (67.6%) suspectedP. aeruginosaisolates showed that 36 (72%) of these isolateswere resistant to one of the used antibiotics,whereasonly 21 (42%) were MDR. The highest percentage of resistance was observedtoceftazidime (66%) followed by ciprofloxacin and levofloxacin (40%). Only 35 isolates were specified by chromogenic agar and 16S rDNAas P. aeruginosa.The minimal inhibitory concentration (MIC) of 35 isolates for ciprofloxacin resistant was between 4 and128 µg/ml while for ceftazidime was between 64and 512 µg/ml. After the addition of 50 μg/ml curcumin with ciprofloxacin, there wasa significant increase in the sensitivity (p≤ 0.01) of 13 MDR P.aeroginosa isolates whereas no differences in the sensitivity to ceftazidime were recorded before and after addition ofcurcumin. In conclusion, the results of this study show that curcumin can decrease the MIC value of ciprofloxacin in MDR isolates of P. aeruginosaand can be used as a native compound to enhance the treatment of resistant isolates with ciprofloxacin.

scholarly journals Genetic characterization of clinical Klebsiella isolates circulating in Novosibirsk

2021 ◽  
Vol 25 (2) ◽  
pp. 234-245
Author(s):  
A. V. Bardasheva ◽  
N. V. Fomenko ◽  
T. V. Kalymbetova ◽  
I. V. Babkin ◽  
S. O. Chretien ◽  
...  
Keyword(s):  
Beta Lactam ◽  
Genetic Determinants ◽  
Aminoglycoside Resistance ◽  
Beta Lactamases ◽  
Phenotypic Resistance ◽  
Molecular Serotyping ◽  
Extended Spectrum ◽  
Extended Spectrum Beta Lactamases ◽  
Aminoglycoside Resistance Genes

72 clinical strains of Klebsiella spp. isolated from samples obtained from humans in Novosibirsk, Russia, were analyzed. Species identification of strains was performed using 16S rRNA and rpoB gene sequences. It was revealed that Klebsiella pneumoniae strains were dominant in the population (57 strains), while the remaining 15 strains were K. grimontii, K. aerogenes, K. oxytoca and K. quasipneumoniae. By molecular serotyping using the wzi gene sequence, K. pneumoniae strains were assigned to twenty-one K-serotypes with a high proportion of virulent K1- and K2-serotypes. It was found that K. pneumoniae strains isolated from the hospitalized patients had a higher resistance to antibiotics compared to the other Klebsiella species. Real-time PCR revealed that the population contained genes of the blaSHV, blaTEM, blaCTX families and the blaOXA-48 gene, which are the genetic determinants of beta-lactam resistance. It has been shown that the presence of the blaCTX sequence correlated with the production of extended-spectrum beta-lactamases, and phenotypic resistance to car-bapenems is due to the presence of the blaOXA-48 gene. At the same time, the carbapenemase genes vim, ndm, kpc, imp were not detected. Among the aminoglycoside resistance genes studied, the aph(6)-Id and aadA genes were found, but their presence did not always coincide with phenotypic resistance. Resistance to fluoroquinolones in the vast majority of strains was accompanied by the presence of the aac(6’)-IB-cr, oqxA, oqxB, qnrB, and qnrS genes in various combinations, while the presence of the oqxA and/or oqxB genes alone did not correlate with resistance to fluoroquinolones. Thus, the detection of blaCTX and blaOXA-48 can be used to quickly predict the production of extended-spectrum beta-lactamases and to determine the resistance of Klebsiella to carbapenems. The detection of the aac(6’)-Ib-cr and/or qnrB/qnrS genes can be used to quickly determine resistance to fluoroquinolones.

First Detection of OXA-10 Extended-Spectrum Beta-Lactamases and the Occurrence of mexR and nfxB in Clinical Isolates of Pseudomonas aeruginosa from Nigeria

Chemotherapy ◽  
2015 ◽  
Vol 61 (2) ◽  
pp. 87-92 ◽  
Author(s):  
Bamidele T. Odumosu ◽  
Bola A. Adeniyi ◽  
Ram Chandra
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Efflux Pump ◽  
Clinical Isolates ◽  
Beta Lactamases ◽  
First Report ◽  
Extended Spectrum ◽  
Pcr Rflp ◽  
Extended Spectrum Beta Lactamases ◽  
Regulator Genes

Background: The characterization of β-lactamase production in Pseudomonasaeruginosa is rarely reported in Nigeria. The objective of this study was to investigate the occurrence and characterize the different β-lactamases as well as mechanisms of fluoroquinolones resistance among P. aeruginosa isolated from various clinical sources from Nigeria. Materials and Method: Isolates were investigated using PCR, RFLP and sequencing for the detection of various β-lactamases and efflux pump regulator genes. Result: The prevalence of OXA-10, AmpC, CTX-M and SHV in P. aeruginosa was 80, 70, 5 and 5%, respectively. The coexistence of blaOXA-10 with blaAmpC, blaSHV and blaCTX-M was reported in 40, 5 and 5% of isolates, respectively. The efflux pump regulator genes mexR and nfxB were both amplified in 45% of the OXA-10-positive isolates. Conclusion: This is the first report of the characterization of OXA-10 extended-spectrum β-lactamases and occurrence of mexR and nfxB efflux regulator genes in clinical isolates of P. aeruginosa in Nigeria.

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