Fluoroquinolone resistance protein NorA of Staphylococcus aureus is a multidrug efflux transporter

Neyfakh, Alexander A.; Borsch, C M; Kaatz, Glenn W.

doi:10.1128/aac.37.1.128

Cited by 321 publications

(232 citation statements)

References 6 publications

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“…aureus is provided by the membrane protein NorA encoded in the bacterial chromosome (12,15). Also, over-expression of…”

Section: Fluoroquinolone Resistance Of Several Clinical Isolates Of Smentioning

confidence: 99%

Effect of galbanic acid, a sesquiterpene coumarin from Ferula szowitsiana, as an inhibitor of efflux mechanism in resistant clinical isolates of Staphylococcus aureus

Bazzaz¹,

Memariani²,

Khashiarmanesh³

et al. 2010

Braz. J. Microbiol.

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Galbanic acid, a sesquiterpene coumarin from Ferula szowitsiana roots, was investigated for its potentiating effect on the antimicrobial activity of antibiotics as well as ethidium bromide, in 6 multidrug resistance (MDR) clinical isolates of Staphylococcus aureus. Galbanic acid had inhibitory effect on none of the isolated bacteria tested (up to 800 µg /ml). The MIC range of ciprofloxacin, tetracycline and ethidium bromide, against all tested S. aureus were 10-80, 10-80 and 4-16 µg/ml, respectively. These were reduced to 2.5-5, 2.5-5 and 0.5-2 µg/ml in the presence of galbanic acid (300 µg /ml) or verapamil (100 µg /ml). The rate of ethidium bromide (2 µg /ml) accumulation in clinical isolates was enhanced with galbanic acid (300 µg /ml). There is also a decrease in loss of ethidium bromide from bacteria in the presence of galbanic acid. Similar results were obtained when verapamil (100 µg /ml) was used as an efflux pump inhibitor. Galbanic acid, like verapamil, a typical inhibitor of efflux pump, reduced the MIC of ethidium bromide and tested antibiotics. Since efflux is the only known reported mechanism for ethidium bromide resistance, the reduction in ethidium bromide MIC and enhanced accumulation as well as decreased efflux of ethidium bromide in the presence of galbanic acid, can be attributed to this efflux inhibitory properties.

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“…aureus is provided by the membrane protein NorA encoded in the bacterial chromosome (12,15). Also, over-expression of…”

Section: Fluoroquinolone Resistance Of Several Clinical Isolates Of Smentioning

confidence: 99%

Effect of galbanic acid, a sesquiterpene coumarin from Ferula szowitsiana, as an inhibitor of efflux mechanism in resistant clinical isolates of Staphylococcus aureus

Bazzaz¹,

Memariani²,

Khashiarmanesh³

et al. 2010

Braz. J. Microbiol.

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“…For example, human P-glycoprotein, the product of the MDR1 gene, is highly homologous to the protein MDR2, which does not efflux drugs but is a specific phosphatidylcholine flippase (6). Similarly, the bacterial multidrug transporters Bmr and Blt of Bacillus subtilis and NorA of Staphylococcus aureus are highly homologous to the efflux transporters whose only known substrate is tetracycline (7)(8)(9)(10).…”

mentioning

confidence: 99%

Efflux of the Natural Polyamine Spermidine Facilitated by the Bacillus subtilis Multidrug Transporter Blt

Woolridge

Vázquez‐Laslop

Markham

et al. 1997

Journal of Biological Chemistry

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Multidrug transporters pump structurally dissimilar toxic molecules out of cells. It is not known, however, if detoxification is the primary physiological function of these transporters. The chromosomal organization of the gene encoding the Bacillus subtilis multidrug transporter Blt suggests a specific function for this protein; it forms a single operon with another gene, bltD, whose protein product is identified here as a spermine/spermidine acetyltransferase, an enzyme catalyzing a key step in spermidine degradation. Overexpression of the Blt transporter in B. subtilis leads not only to the multidrug-resistance phenotype but also to the efflux of large amounts of spermidine into the medium; this efflux is supressed by an inhibitor of Blt, reserpine. Taken together, these results strongly suggest that the natural function of the Blt transporter is the efflux of spermidine, whereas multiple drugs may be recognized by Blt merely opportunistically.Multidrug transporters, first discovered in mammalian cells (P-glycoprotein) (1) and later found in yeast (2) and many species of bacteria (3-5), pump structurally dissimilar toxic molecules, including many anticancer, antifungal, and antibacterial agents, out of cells. The ability of each multidrug transporter to recognize dozens of compounds that have no apparent structural consensus seemingly contradicts basic dogmas of biochemistry and remains enigmatic.Another unresolved question associated with multidrug transporters concerns their normal physiological functions. Because overexpression of these proteins causes an increase in cellular resistance to toxins, it is commonly believed that they have evolved to protect cells from diverse environmental toxic molecules. It is possible, however, that each multidrug transporter has a specific, presently unidentified natural substrate, e.g. some cellular metabolite, whereas multiple drugs are effluxed by them merely opportunistically. This latter hypothesis is indirectly supported by the analysis of the primary structures of multidrug transporters. More than two dozen known transporters capable of effluxing multiple drugs share no common sequence motif and belong to at least four distinct superfamilies of membrane proteins (1-5). Furthermore, many multidrug transporters display strong homology to substrate-specific transporters. For example, human P-glycoprotein, the product of the MDR1 gene, is highly homologous to the protein MDR2, which does not efflux drugs but is a specific phosphatidylcholine flippase (6). Similarly, the bacterial multidrug transporters Bmr and Blt of Bacillus subtilis and NorA of Staphylococcus aureus are highly homologous to the efflux transporters whose only known substrate is tetracycline (7-10).It has recently been demonstrated that P-glycoprotein transports not only drugs but also structurally diverse natural lipids across the membrane (11). Here we demonstrate that the activity of the B. subtilis multidrug transporter Blt leads to the efflux of a natural cellular constituent, the polyamine spermi...

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“…an increase in MIC, has been attributed mainly to the excretion of drugs into the extracellular space by proton motive forcedependent multidrug-transport systems (Grinius et al, 1992;Kaatz et al, 1993;. In S. aureus, qacA (Rouch et al, 1990), qacB (Paulsen et al, 1996), smr (Grinius et al, 1992) and norA (Neyfakh et al, 1993), which encode multidrug-transporter proteins, have been identified as antiseptic-resistance genes which confer resistance to cationic antiseptic agents including dyes such as acriflavine, acrinol and ethidium bromide, quaternary ammonium compounds (QACs) such as benzethonium chloride and benzalkonium chloride, and biguanides such as chlorhexidine digluconate (Littlejohn et al, 1992;. Therefore, an MRSA strain with decreased suscept-ibility to antiseptic agents mediated by an antiseptic-resistance gene is interpreted as an antiseptic-resistant strain (Lyon & Skurry, 1987).…”

Section: Introductionmentioning

confidence: 99%

Susceptibilities to antiseptic agents and distribution of antiseptic-resistance genes qacA/B and smr of methicillin-resistant Staphylococcus aureus isolated in Asia during 1998 and 1999

Noguchi

Suwa

Narui

et al. 2005

Journal of Medical Microbiology

147

110

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Many antiseptic agents are used in hygienic handwashes in the prevention of nosocomial infections by methicillin-resistant Staphylococcus aureus (MRSA). The plasmid-borne genes qacA/B and smr confer resistance to cationic antiseptic agents in S. aureus. In this study, the susceptibilities for dyes and antiseptic agents (e.g. acriflavine, acrinol, benzalkonium chloride, benzethonium chloride, chlorhexidine digluconate and alkyldiaminoethylglycine hydrochloride) of 894 isolates of MRSA collected from 11 Asian countries (South Korea, China, the Philippines, Singapore, Vietnam, Thailand, Indonesia, India, Sri Lanka, Saudi Arabia and Japan) between 1998 and 1999 were examined. In addition, the distributions of the antiseptic-resistance genes qacA/B and smr were studied by PCR. Among the Asian MRSA isolates 57 . 7 % (516/894) were acriflavine-resistant. The smr gene was detected in 31 . 6 % (12/38) of MRSA isolates from India but only in 1 . 9 % (16/856) of all the isolates from other Asian countries. MRSA with qacA/B comprised 41 . 6 % (372/894) of the isolates across Asia. In addition, PFGE was performed to type the MRSA and grouped the tested 30 MRSA isolates with qacA/B into 21 PFGE types. The results indicated that qacA/B is functionally the most important gene mediating antiseptic resistance in the MRSA strains of Asia and that a specific MRSA with qacA/B was not prevalent in Asia but qacA/B were widely spread among MRSA of Asia, while the geographical distribution of smr is more limited.

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Fluoroquinolone resistance protein NorA of Staphylococcus aureus is a multidrug efflux transporter

Cited by 321 publications

References 6 publications

Effect of galbanic acid, a sesquiterpene coumarin from Ferula szowitsiana, as an inhibitor of efflux mechanism in resistant clinical isolates of Staphylococcus aureus

Effect of galbanic acid, a sesquiterpene coumarin from Ferula szowitsiana, as an inhibitor of efflux mechanism in resistant clinical isolates of Staphylococcus aureus

Efflux of the Natural Polyamine Spermidine Facilitated by the Bacillus subtilis Multidrug Transporter Blt

Susceptibilities to antiseptic agents and distribution of antiseptic-resistance genes qacA/B and smr of methicillin-resistant Staphylococcus aureus isolated in Asia during 1998 and 1999

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