AcrB Multidrug Efflux Pump of
            <i>Escherichia coli</i>
            : Composite Substrate-Binding Cavity of Exceptional Flexibility Generates Its Extremely Wide Substrate Specificity

Yu, Edward; Aires, Julio; Nikaido, Hiroshi

doi:10.1128/jb.185.19.5657-5664.2003

Cited by 168 publications

(155 citation statements)

References 50 publications

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“…Doxorubicin is produced inside S. peucetius cells; therefore, presumably the function of the DrrAB system is to remove it from the cytoplasmic compartment to the outside. Being amphipathic, however, Dox could conceivably partition into the cell membrane and then be picked up by the DrrB protein directly from the membrane, as suggested in an early model proposed for AcrB function (8). This strategy for its removal could also provide protection to the cell from the toxic effects of free Dox inside the cell.…”

Section: Discussionmentioning

confidence: 99%

“…2) how and why does MDR evolve? Extensive biochemical analysis of Pgp (1,4,5) as well as the availability of three-dimensional structures of the drug-bound forms of Pgp, AcrB, BmrR, and QacR (6,8,43,44) has contributed significantly to understanding the molecular basis of poly-specific drug binding. These studies indicate that the MDR proteins contain an extensive (and flexible) drug binding pocket that can accommodate multiple drugs simultaneously via interactions with specific (sometimes overlapping) aromatic and polar residues present in different parts of the pocket.…”

Section: Discussionmentioning

confidence: 99%

“…The crystal structure of another MDR protein, AcrB, a secondary-active transporter, is also available. This structure also showed the presence of a very large central drug binding cavity, which could accommodate several ligand molecules simultaneously (8). However, the drug binding cavity, although present in the membrane, was found to be accessible to the periplasmic domain.…”

Section: Multidrug Resistance (Mdr)mentioning

confidence: 99%

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The DrrAB Efflux System of Streptomyces peucetius Is a Multidrug Transporter of Broad Substrate Specificity

Sharma

Kaur

2014

Journal of Biological Chemistry

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Background: DrrAB is dedicated to export of doxorubicin in Streptomyces peucetius, an organism that produces this anticancer drug. Whether this prototype system can export other drugs has not been investigated. Results: DrrAB exports multiple drugs efficiently. Conclusion: Substrate specificity of DrrAB overlaps with known bacterial and human multidrug resistance proteins. Significance: This study suggests common mechanisms and origin for DrrAB and other MDR proteins.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Multidrug Resistance (Mdr)mentioning

confidence: 99%

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The DrrAB Efflux System of Streptomyces peucetius Is a Multidrug Transporter of Broad Substrate Specificity

Sharma

Kaur

2014

Journal of Biological Chemistry

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“…Aromatic residues are expected to play a key role in drug binding in all multidrug-binding proteins, given their ability to stack with aromatic drugs and be involved in electrostatic interactions with charged drugs (22)(23)(24)(25). Indeed, the crystal structure of the transcription activator, BmrR, with an aromatic monovalent cation (26,27) and the recent moderate-resolution crystal structures of four drugs bound to the bacterial multidrug transporter AcrB, also showed the importance of such interactions (28,29). The structures of the odorant-binding protein, a polyspecific multiligand-binding protein, in complex with multiple small nonpolar and aromatic compounds also demonstrate a central role for aromatic residues in ligand binding (30,31).…”

Section: Discussionmentioning

confidence: 99%

Crystal Structures of QacR-Diamidine Complexes Reveal Additional Multidrug-binding Modes and a Novel Mechanism of Drug Charge Neutralization

Murray¹,

Schumacher²,

Brennan

2004

Journal of Biological Chemistry

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The Staphylococcus aureus multidrug-binding protein QacR represses transcription of the plasmid-encoded membrane protein QacA, a multidrug efflux transporter. QacR is induced by multiple structurally dissimilar monovalent and bivalent cationic lipophilic compounds, many of which are effluxed from the cell by QacA via the proton motive force. The multidrug-binding pocket of QacR has been shown to be quite extensive and features several glutamates and multiple aromatic residues. To date, the structure of only one QacR-bivalent cationic drug complex (that of QacR bound to dequalinium) has been determined, and how other longer or shorter bivalent cationic compounds bind is unknown. Here we report the crystal structures of QacR bound to two cytotoxic bivalent diamidines, pentamidine and hexamidine. These compounds are structurally similar, differing by only one methylene carbon in the alkyl chain linker. However, this small difference results in very dissimilar binding modes. Similar to dequalinium, hexamidine spans the multidrug-binding pocket, and its positively charged benzamidine groups are neutralized by residues Glu-57 and Glu-120. Pentamidine binds QacR in a novel fashion whereby one of its benzamidine groups interacts with residue Glu-63, and the other is neutralized by carbonyl and side chain oxygen atoms. Thus, these structures demonstrate that a formal negative charge is not a prerequisite for binding positively charged drugs and underscore the versatility of the QacR and, likely, all multidrug-binding pockets.

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“…The ESBLs enzyme confers resistance not only to broad-spectrum cephalosporins, including oxymino-β-lactam antibiotics, but also to other commonly used antibiotics, including aminoglycosides and quinolone [33,34]. Overexpression of elux pump is often associated with extrusion of most of the β-lactam antibiotics, leading to decreased susceptibility of antibiotics [35].…”

Section: Antibiotic Resistancementioning

confidence: 99%

Advancing in the Direction of Right Solutions: Treating Multidrug-Resistant Pneumonia

Chaudhary¹,

Ayub²,

Payasi³

2017

Contemporary Topics of Pneumonia

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Worldwide, antibiotic resistance is a major contemporary public health threat due to rapid emergence of resistant bacteria and endangering the eicacy of antibiotics. There are signiicant number of reports on clinical failure of β-lactam and β-lactamase inhibitor combination and even carbapenems due to various carbapenem resistance mechanisms. The increasing rate of the antibiotic resistance and its impact on treatment failure encouraged us to study newly reported concept of antibiotic adjuvant entities (AAEs) by which the increasing failure rate of antibiotics can be controlled. These AAEs have been developed for both Gram-positive and Gram-negative multidrug-resistant (MDR) infections. Elores (ceftriaxone + sulbactam with adjuvant ethylenediaminetetraacetic acid (EDTA)) and Potentox (cefepime + amikacin with adjuvant potassium chloride) are the AAEs for Gram-negative MDR pathogens each catering to a diferent type of resistance and Vancoplus (ceftriaxone + vancomycin with adjuvant L-arginine), another AAE, can help us to last longer in the war against antibiotic-resistant Gram-positive bugs particularly which cause complicated lower respiratory tract infection (LRTI) leading to pneumonia. These new antibiotic additions (Elores, Potentox, and Vancoplus) to the current armamentarium to treat MDR infections, including pneumonia, can help us combat against antimicrobial resistance more eiciently.

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AcrB Multidrug Efflux Pump of Escherichia coli : Composite Substrate-Binding Cavity of Exceptional Flexibility Generates Its Extremely Wide Substrate Specificity

Cited by 168 publications

References 50 publications

The DrrAB Efflux System of Streptomyces peucetius Is a Multidrug Transporter of Broad Substrate Specificity

The DrrAB Efflux System of Streptomyces peucetius Is a Multidrug Transporter of Broad Substrate Specificity

Crystal Structures of QacR-Diamidine Complexes Reveal Additional Multidrug-binding Modes and a Novel Mechanism of Drug Charge Neutralization

Advancing in the Direction of Right Solutions: Treating Multidrug-Resistant Pneumonia

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