Control of the AcrAB multidrug efflux pump by quorum-sensing regulator SdiA

Biofilm formation in healthcare is an issue of considerable concern, as it results in increased morbidity and mortality, imposing a significant financial burden on the healthcare system. Biofilms are highly resistant to conventional antimicrobial therapies and lead to persistent infections. Hence, there is a high demand for novel strategies other than conventional antibiotic therapies to control biofilm-based infections. There are two approaches which have been employed so far to control biofilm formation in healthcare settings: one is the development of biofilm inhibitors based on the understanding of the molecular mechanism of biofilm formation, and the other is to modify the biomaterials which are used in medical devices to prevent biofilm formation. This review will focus on the recent advances in anti-biofilm approaches by interrupting the quorum-sensing cellular communication system and the multidrug efflux pumps which play an important role in biofilm formation. Research efforts directed towards these promising strategies could eventually lead to the development of better anti-biofilm therapies than the conventional treatments.

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Candida albicans Zn Cluster Transcription Factors Tac1 and Znc1 Are Activated by Farnesol To Upregulate a Transcriptional Program Including the Multidrug Efflux Pump CDR1

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00968-18 ◽

2018 ◽

Vol 62 (11) ◽

Cited By ~ 2

Author(s):

Zhongle Liu ◽

John M. Rossi ◽

Lawrence C. Myers

Keyword(s):

Candida Albicans ◽

Transcription Factors ◽

Quorum Sensing ◽

Efflux Pump ◽

Close Relative ◽

Multidrug Efflux ◽

Multidrug Efflux Pump ◽

Content Type ◽

Dna Binding Specificity ◽

Hyphal Formation

ABSTRACT Farnesol, a quorum-sensing molecule, inhibits Candida albicans hyphal formation, affects its biofilm formation and dispersal, and impacts its stress response. Several aspects of farnesol's mechanism of action remain incompletely uncharacterized. Among these are a thorough accounting of the cellular receptors and transporters for farnesol. This work suggests these processes are linked through the Zn cluster transcription factors Tac1 and Znc1 and their induction of the multidrug efflux pump Cdr1. Specifically, we have demonstrated that Tac1 and Znc1 are functionally activated by farnesol through a mechanism that mimics other means of hyperactivation of Zn cluster transcription factors. This is consistent with our observation that many genes acutely induced by farnesol are dependent on TAC1, ZNC1, or both. A related molecule, 1-dodecanol, invokes a similar TAC1-ZNC1 response, while several other proposed C. albicans quorum-sensing molecules do not. Tac1 and Znc1 both bind to and upregulate the CDR1 promoter in response to farnesol. Differences in inducer and DNA binding specificity lead to Tac1 and Znc1 having overlapping, but nonidentical, regulons. Induction of genes by farnesol via Tac1 and Znc1 was inversely related to the level of CDR1 present in the cell, suggesting a model in which induction of CDR1 by Tac1 and Znc1 leads to an increase in farnesol efflux. Consistent with this premise, our results show that CDR1 expression, and its regulation by TAC1 and ZNC1, facilitates growth in the presence of high farnesol concentrations in C. albicans and in certain strains of its close relative, C. dubliniensis.

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Control of Quorum Sensing by a Burkholderia pseudomallei Multidrug Efflux Pump

Journal of Bacteriology ◽

10.1128/jb.00003-07 ◽

2007 ◽

Vol 189 (11) ◽

pp. 4320-4324 ◽

Cited By ~ 57

Author(s):

Ying Ying Chan ◽

Hao Sheng Bian ◽

Theresa May Chin Tan ◽

Margrith E. Mattmann ◽

Grant D. Geske ◽

...

Keyword(s):

Quorum Sensing ◽

Burkholderia Pseudomallei ◽

Efflux Pump ◽

Homoserine Lactone ◽

Multidrug Efflux ◽

Multidrug Efflux Pump ◽

Homoserine Lactones ◽

Extracellular Secretion ◽

Sensing Systems ◽

Acyl Homoserine Lactones

ABSTRACT The Burkholderia pseudomallei KHW quorum-sensing systems produced N-octanoyl-homoserine lactone, N-decanoyl-homoserine lactone, N-(3-hydroxy)-octanoyl-homoserine lactone, N-(3-hydroxy)-decanoyl-homoserine lactone, N-(3-oxo)-decanoyl-homoserine lactone, and N-(3-oxo)-tetradecanoyl-homoserine lactone. The extracellular secretion of these acyl-homoserine lactones is dependent absolutely on the function of the B. pseudomallei BpeAB-OprB efflux pump.

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Faculty Opinions recommendation of Structure of the AcrAB-TolC multidrug efflux pump.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718356663.793495679 ◽

2014 ◽

Author(s):

Paul Savage

Keyword(s):

Efflux Pump ◽

Multidrug Efflux ◽

Multidrug Efflux Pump

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Faculty Opinions recommendation of Molecular basis for inhibition of AcrB multidrug efflux pump by novel and powerful pyranopyridine derivatives.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726218324.793516072 ◽

2016 ◽

Author(s):

Herschel Wade

Keyword(s):

Molecular Basis ◽

Efflux Pump ◽

Multidrug Efflux ◽

Multidrug Efflux Pump

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Faculty Opinions recommendation of Biased partitioning of the multidrug efflux pump AcrAB-TolC underlies long-lived phenotypic heterogeneity.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.727537002.793532571 ◽

2017 ◽

Author(s):

Chris Whitfield

Keyword(s):

Efflux Pump ◽

Phenotypic Heterogeneity ◽

Multidrug Efflux ◽

Multidrug Efflux Pump

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Molecular Insights into an Antibiotic Enhancer Action of New Morpholine-Containing 5-Arylideneimidazolones in the Fight against MDR Bacteria

International Journal of Molecular Sciences ◽

10.3390/ijms22042062 ◽

2021 ◽

Vol 22 (4) ◽

pp. 2062

Author(s):

Aneta Kaczor ◽

Karolina Witek ◽

Sabina Podlewska ◽

Veronique Sinou ◽

Joanna Czekajewska ◽

...

Keyword(s):

Molecular Modelling ◽

Efflux Pump ◽

Gram Negative Bacteria ◽

Potential Mechanism ◽

Multidrug Efflux ◽

Aromatic Rings ◽

Allosteric Site ◽

Multidrug Efflux Pump ◽

Dual Action

In the search for an effective strategy to overcome antimicrobial resistance, a series of new morpholine-containing 5-arylideneimidazolones differing within either the amine moiety or at position five of imidazolones was explored as potential antibiotic adjuvants against Gram-positive and Gram-negative bacteria. Compounds (7–23) were tested for oxacillin adjuvant properties in the Methicillin-susceptible S. aureus (MSSA) strain ATCC 25923 and Methicillin-resistant S. aureus MRSA 19449. Compounds 14–16 were tested additionally in combination with various antibiotics. Molecular modelling was performed to assess potential mechanism of action. Microdilution and real-time efflux (RTE) assays were carried out in strains of K. aerogenes to determine the potential of compounds 7–23 to block the multidrug efflux pump AcrAB-TolC. Drug-like properties were determined experimentally. Two compounds (10, 15) containing non-condensed aromatic rings, significantly reduced oxacillin MICs in MRSA 19449, while 15 additionally enhanced the effectiveness of ampicillin. Results of molecular modelling confirmed the interaction with the allosteric site of PBP2a as a probable MDR-reversing mechanism. In RTE, the compounds inhibited AcrAB-TolC even to 90% (19). The 4-phenylbenzylidene derivative (15) demonstrated significant MDR-reversal “dual action” for β-lactam antibiotics in MRSA and inhibited AcrAB-TolC in K. aerogenes. 15 displayed also satisfied solubility and safety towards CYP3A4 in vitro.

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Correlation between the Antibiotic Resistance Genes and Susceptibility to Antibiotics among the Carbapenem-Resistant Gram-Negative Pathogens

Antibiotics ◽

10.3390/antibiotics10030255 ◽

2021 ◽

Vol 10 (3) ◽

pp. 255

Author(s):

Salma M. Abdelaziz ◽

Khaled M. Aboshanab ◽

Ibrahim S. Yahia ◽

Mahmoud A. Yassien ◽

Nadia A. Hassouna

Keyword(s):

Antibiotic Resistance ◽

Resistance Genes ◽

Efflux Pump ◽

Antibiotic Resistance Genes ◽

Multiple Drug ◽

P Value ◽

Multidrug Efflux ◽

Multidrug Efflux Pump ◽

Gram Negative ◽

Carbapenem Resistant

In this study, the correlation between the antibiotic resistance genes and antibiotic susceptibility among the carbapenem-resistant Gram-negative pathogens (CRGNPs) recovered from patients diagnosed with acute pneumonia in Egypt was found. A total of 194 isolates including Klebsiella pneumoniae (89; 46%), Escherichia coli (47; 24%) and Pseudomonas aeruginosa (58; 30%) were recovered. Of these, 34 (18%) isolates were multiple drug resistant (MDR) and carbapenem resistant. For the K. pneumoniae MDR isolates (n = 22), blaNDM (14; 64%) was the most prevalent carbapenemase, followed by blaOXA-48 (11; 50%) and blaVIM (4; 18%). A significant association (p value < 0.05) was observed between the multidrug efflux pump (AcrA) and resistance to β-lactams and the aminoglycoside acetyl transferase gene (aac-6’-Ib) gene and resistance to ciprofloxacin, azithromycin and β-lactams (except for aztreonam). For P. aeruginosa, a significant association was noticed between the presence of the blaSHV gene and the multidrug efflux pump (MexA) and resistance to fluoroquinolones, amikacin, tobramycin, co-trimoxazole and β-lactams and between the aac-6’-Ib gene and resistance to aminoglycosides. All P. aeruginosa isolates (100%) harbored the MexAB-OprM multidrug efflux pump while 86% of the K. pneumoniae isolates harbored the AcrAB-TolC pump. Our results are of great medical importance for the guidance of healthcare practitioners for effective antibiotic prescription.

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