Sequence similarity between macrolide-resistance determinants and ATP-binding transport proteins

Schoner, Brigitte E.; Geistlich, Martin; Rosteck, Paul R.; Rao, Rosa; Seno, Eugene T.; Reynolds, Patricia; Cox, Karen L.; Burgett, Stanley G.; Hershberger, Charles L.

doi:10.1016/0378-1119(92)90545-z

Cited by 88 publications

(55 citation statements)

References 18 publications

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“…The frequent occurrence of more than a single resistance gene within or outside the cluster of structural and regulatory genes in producing organisms attests to this fact (9). For example, tylosin resistance in Streptomyces fradiae involves both target site modification (47,48) and apparent export mechanisms (39,42) mediated by the tlrAD and tlrBC genes, respectively. Resistance to actinorhodin (15) and tetracenomycin (18), in contrast, appears to involve a single transportmediated mechanism, which in the case of actinorhodin has been shown to be essential for antibiotic export (15).…”

Section: Discussionmentioning

confidence: 99%

The Streptomyces peucetius drrC gene encodes a UvrA-like protein involved in daunorubicin resistance and production

et al. 1996

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The drrC gene, cloned from the daunorubicin (DNR)-and doxorubicin-producing strain of Streptomyces peucetius ATCC 29050, encodes a 764-amino-acid protein with a strong sequence similarity to the Escherichia coli and Micrococcus luteus UvrA proteins involved in excision repair of DNA. Expression of drrC was correlated with the timing of DNR production in the growth medium tested and was not dependent on the presence of DNR. Since introduction of drrC into Streptomyces lividans imparted a DNR resistance phenotype, this gene is believed to be a DNR resistance gene. The drrC gene could be disrupted in the non-DNR-producing S. peucetius dnrJ mutant but not in the wild-type strain, and the resulting dnrJ drrC double mutant was significantly more sensitive to DNR in efficiency-of-plating experiments. Expression of drrC in an E. coli uvrA strain conferred significant DNR resistance to this highly DNR-sensitive mutant. However, the DrrC protein did not complement the uvrA mutation to protect the mutant from the lethal effects of UV or mitomycin even though it enhanced the UV resistance of a uvrA ؉ strain. We speculate that the DrrC protein mediates a novel type of DNR resistance, possibly different from the mechanism of DNR resistance governed by the S. peucetius drrAB genes, which are believed to encode a DNR antiporter.Microorganisms require one or more self-resistance determinants to produce antibiotics, except in cases in which they are insensitive to the antibiotic's effect(s). The resistance genes usually are clustered with the structural (biosynthetic) and regulatory genes and encode proteins that either inactivate the antibiotic, facilitate its export, or modify the host to render it insensitive to the antibiotic (9). Multiple rather than single resistance mechanisms are often found; in this case, it is not known whether any one resistance mode is sufficient to ensure survival or antibiotic production. We address this question here.Streptomyces peucetius, which produces the important antitumor drugs daunorubicin (DNR) (4, 10) and doxorubicin (DXR) (2), contains the drrAB (17) and ric2 (8) resistance genes, which are assumed to provide self-resistance to these two antibiotics because they confer DNR and DXR resistance when introduced into Streptomyces lividans. The DrrA protein strongly resembles bacterial proteins that transport compounds by an ATP-dependent process (20), as well as the Mdr1 P glycoprotein responsible for DNR-DXR resistance of human cancer cells and known to act as an ATP-dependent transporter (19). DrrA thus is a candidate for a DNR-DXR binding and transport protein, whereas the hydrophobic DrrB protein could be responsible for binding DrrA to the bacterial membrane. The ric2 locus, which unlike drrAB is not part of the cluster of DXR production genes (8), may also be important for self-resistance. A third gene, drrC, in the same cluster of genes as is drrAB, encodes the DrrC protein described here. S. lividans drrC ϩ transformants display a DNR resistance phenotype similar to that of drrAB tran...

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Section: Discussionmentioning

confidence: 99%

The Streptomyces peucetius drrC gene encodes a UvrA-like protein involved in daunorubicin resistance and production

et al. 1996

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“…These organisms need efficient resistance mechanisms to protect them against the antibiotics they produce. Several macrolide resistance genes have been isolated, including car(A) from Streptomyces thermotolerans, srm(B) from Streptomyces ambofaciens, and tlr(C) from Streptomyces fradiae, which confer resistance to the 16-membered-ring macrolides carbomycin, spiramycin, and tylosin, respectively (428). In Streptomyces antibioticus, which produces the 14-memberedring macrolide oleandomycin, the ole(B) gene confers resistance to oleandomycin in the heterologous hosts Streptomyces albus and S. lividans (342).…”

Section: Art Family Of Proteins With Diverse Functionsmentioning

confidence: 99%

Structure, Function, and Evolution of Bacterial ATP-Binding Cassette Systems

Davidson

Dassa

Orelle

et al. 2008

Microbiol Mol Biol Rev

1,139

1,137

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SUMMARY ATP-binding cassette (ABC) systems are universally distributed among living organisms and function in many different aspects of bacterial physiology. ABC transporters are best known for their role in the import of essential nutrients and the export of toxic molecules, but they can also mediate the transport of many other physiological substrates. In a classical transport reaction, two highly conserved ATP-binding domains or subunits couple the binding/hydrolysis of ATP to the translocation of particular substrates across the membrane, through interactions with membrane-spanning domains of the transporter. Variations on this basic theme involve soluble ABC ATP-binding proteins that couple ATP hydrolysis to nontransport processes, such as DNA repair and gene expression regulation. Insights into the structure, function, and mechanism of action of bacterial ABC proteins are reported, based on phylogenetic comparisons as well as classic biochemical and genetic approaches. The availability of an increasing number of high-resolution structures has provided a valuable framework for interpretation of recent studies, and realistic models have been proposed to explain how these fascinating molecular machines use complex dynamic processes to fulfill their numerous biological functions. These advances are also important for elucidating the mechanism of action of eukaryotic ABC proteins, because functional defects in many of them are responsible for severe human inherited diseases.

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“…Moreover, these bacteria synthesize proteins that render them resistant to the antibiotics they produce. Horizontal transmission of the genetic material encoding these proteins is apparently in part responsible for the spread of drug resistance in bacterial populations (Mosher & Vining, 1992 ;Parr & Saier, 1992 ;Reizer e t al., 1992b ;Schoner et al, 1992). In order to understand the interrelationships between the syntheses of secondary metabolites and the metabolism of carbohydrates in these Abbreviations: DTP, diphosphoryl transfer protein; -P, phosphate; PEP, phosphoenolpyruvate; PTS, phosphotransferase system; TMG, thiomethyl B-galactoside (methyl /h-thiogalactopyranoside).…”

Section: Introductionmentioning

confidence: 99%

Identification and characterization of phosphoenolpyruvate: fructose phosphotransferase systems in three Streptomyces species

et al. 1995

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Streptomyces liwidans, S. coelicolor and S. griseohscus were examined for the presence of the enzymes of the phosphoenolpyruvate : sugar phosphotransferase system (PTS). All three species were shown to possess Enzyme I, HPr and fructose-specific Enzyme II (IIFN) activities. In 5. liwidans and 5. coelicolor, all three PTS enzymes were fructose-inducible, but in 5. griseokrscus the system was expressed constitutively. These organisms apparently lack the HPr(Ser) kinase and HPr(Ser-P) phosphatase that characterize low-GC Gram-positive bacteria.

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Sequence similarity between macrolide-resistance determinants and ATP-binding transport proteins

Cited by 88 publications

References 18 publications

The Streptomyces peucetius drrC gene encodes a UvrA-like protein involved in daunorubicin resistance and production

The Streptomyces peucetius drrC gene encodes a UvrA-like protein involved in daunorubicin resistance and production

Structure, Function, and Evolution of Bacterial ATP-Binding Cassette Systems

Identification and characterization of phosphoenolpyruvate: fructose phosphotransferase systems in three Streptomyces species

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