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Yumi Park Qute Choi Gye Cheol Kwon Sun Hoe Koo 《Journal of clinical laboratory analysis》2020,34(12):e23506
BackgroundThe emergence and transmission of tigecycline‐ and carbapenem‐resistant Klebsiella pneumoniae (TCRKP) have become a major concern to public health globally. Here, we investigated the molecular epidemiology and mechanisms of tigecycline resistance in carbapenem‐resistant K pneumoniae (CRKP) isolates.MethodsForty‐five non‐duplicate CRKP isolates were collected from January 2017 to June 2019. We performed antimicrobial susceptibility tests, multilocus sequence typing (MLST), and pulsed‐field gel electrophoresis (PFGE). PCR and DNA sequencing were performed for the detection and mutation analysis of acrR, oqxR, ramR, rpsJ, tet(A), and tet(X) genes, which are related to tigecycline resistance. The expression levels of efflux pump genes acrB and oqxB and their regulator genes rarA, ramA, soxS, and marA were assessed by quantitative real‐time PCR.ResultsThe resistance rate to tigecycline in CRKP isolates was 37.8% (17/45). K pneumoniae ST307 was a predominant clone type (70.6%, 12/17) among the TCRKP isolates. The expression levels of acrB (P < .001) and marA (P = .009) were significantly higher in the tigecycline‐resistant group than in the tigecycline‐intermediate and tigecycline‐susceptible groups. Increased expression of acrB was associated with marA expression (r = 0.59, P = .013).ConclusionsWe found that the activated MarA‐induced overexpression of AcrAB efflux pump plays an important role in the emergence of tigecycline resistance in CRKP isolates. 相似文献
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Arijit Pal Anusri Tripathi 《APMIS : acta pathologica, microbiologica, et immunologica Scandinavica》2020,128(3):251-259
Rapid dissemination of carbapenem-resistant Gram-negative bacteria (CRGNB) is a global threat. Quercetin is known for its antimicrobial activity. In this study, carbapenemase and efflux pump inhibitory activities of quercetin were demonstrated against carbapenem-resistant Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii. Further, molecular docking was performed to elucidate molecular mechanisms of such inhibition. CRGNB, expressing one of the carbapenemases, demonstrated significant inhibition of carbapenemase activity when pre-incubated with 64 µg/ml quercetin. Moreover, acrB overexpressing enterobacterial isolates exhibited significant inhibition of efflux activity upon quercetin treatment. Molecular docking studies revealed stability of quercetin-carbapenemase complexes. (i) Virtual superimposition of quercetin onto meropenem, (ii) proximity of quercetin to attacking nucleophile and (iii) involvement of same amino acids that stabilize both meropenem and quercetin – indicated competition between quercetin and meropenem for ligand binding. Although quercetin and PAβN, a standard efflux pump inhibitor, docked at both central cavity and periplasmic drug binding sites of AcrB, they did not virtually superimpose on each other. However, sufficient release of Gibb's free energy and involvement of same set of amino acids in PAβN and quercetin stability predicted quercetin's efflux pump inhibitory potential. Hence, quercetin could be potential adjuvant therapeutics for CRGNB-mediated infections. 相似文献
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Naomasa Gotoh Takeshi Murata Toru Ozaki Tadashi Kimura Akiko Kondo Takeshi Nishino 《Journal of infection and chemotherapy》2003,9(1):101-103
Intrinsic resistance to mureidomycin is shown in Escherichia coli. This is in contrast to Pseudomonas aeruginosa, which generally displays intrinsic resistance to a variety of antimicrobial agents, but not to mureidomycin. Isogenic efflux
system mutants from both species were subjected to antibiotic susceptibility tests. These studies showed that the differences
regarding the susceptibility of E. coli and P. aeruginosa to mureidomycin A and C may be explained by the expression of efflux systems that mediate resistance to mureidomycin A and
C.
Received: July 22, 2002 / Accepted: September 24, 2002
Acknowledgments We thank Masatoshi Inukai (Sankyo Co., Japan) for providing mureidomycin A and C, and we thank Keith Poole (Queen's University,
Canada) and Jun-ichi Yamagishi (Dainippon Pharmaceutical Co., Japan) for providing the K and SH strains of E. coli, respectively. This research was supported by grants for scientific research to N.G. from The Ministry of Education, Culture,
Sports, Science, and Technology (MEXT) of Japan, and from the Ministry of Health, Labor, and Welfare of Japan. T.M. was the
recipient of a scholarship from The Japan Scholarship Foundation. 相似文献
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Andraž Lamut Lucija Peterlin Mašič Danijel Kikelj Tihomir Tomašič 《Medicinal research reviews》2019,39(6):2460-2504
Bacterial infections are an increasingly serious issue worldwide. The inability of existing therapies to treat multidrug-resistant pathogens has been recognized as an important challenge of the 21st century. Efflux pumps are important in both intrinsic and acquired bacterial resistance and identification of small molecule efflux pump inhibitors (EPIs), capable of restoring the effectiveness of available antibiotics, is an active research field. In the last two decades, much effort has been made to identify novel EPIs. However, none of them has so far been approved for therapeutic use. In this article, we explore different structural families of currently known EPIs for multidrug resistance efflux systems in the most extensively studied pathogens (NorA in Staphylococcus aureus, AcrAB-TolC in Escherichia coli, and MexAB-OprM in Pseudomonas aeruginosa). Both synthetic and natural compounds are described, with structure-activity relationship studies and optimization processes presented systematically for each family individually. In vitro activities against selected test strains are presented in a unifying manner for all the EPIs described, together with the most important toxicity, pharmacokinetic and in vivo efficacy data. A critical evaluation of lead-likeness characteristics and the potential for clinical development of the most promising inhibitors of the three efflux systems is described. This overview of EPIs is a good starting point for the identification of novel effective antibacterial drugs. 相似文献
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