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

Li, Wen; Sharma, Madhu; Kaur, Parjit

doi:10.1074/jbc.m113.536136

Cited by 52 publications

(71 citation statements)

References 68 publications

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“…We demonstrated substrate polyspecificity in a homologous group of ABC efflux systems that can confer resistance against a spectrum of structurally distinct antibiotics and anticancer drugs. These probable two-component transporters all display moderate sequence homology (30 to 50% shared identity) against the DrrAB multidrug efflux system of the DAU-/DOX-producing Streptomyces peucetius (31) and are predicted to originate from bacteria of diverse phyla, including Actinobacteria, Firmicutes, and Proteobacteria (see Table S3 in the supplemental material). While the identification of novel DrrAB homologues in different bacterial taxa is not unexpected, the ligand promiscuity of these functionally conserved, but sequence-wise diverse, ABC transporters (DrrAB included) raises insightful questions of what drove the development of polyspecific substrate recognition and whether these transporters have shared evolutionary history with similar multidrug efflux system found in now-pathogenic organisms.…”

Section: Figmentioning

confidence: 99%

Novel Antibiotic Resistance Determinants from Agricultural Soil Exposed to Antibiotics Widely Used in Human Medicine and Animal Farming

Lau

Engelen

Gordon

et al. 2017

Appl Environ Microbiol

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Antibiotic resistance has emerged globally as one of the biggest threats to human and animal health. Although the excessive use of antibiotics is recognized as accelerating the selection for resistance, there is a growing body of evidence suggesting that natural environments are "hot spots" for the development of both ancient and contemporary resistance mechanisms. Given that pharmaceuticals can be entrained onto agricultural land through anthropogenic activities, this could be a potential driver for the emergence and dissemination of resistance in soil bacteria. Using functional metagenomics, we interrogated the "resistome" of bacterial communities found in a collection of Canadian agricultural soil, some of which had been receiving antibiotics widely used in human medicine (macrolides) or food animal production (sulfamethazine, chlortetracycline, and tylosin) for up to 16 years. Of the 34 new antibiotic resistance genes (ARGs) recovered, the majority were predicted to encode (multi)drug efflux systems, while a few share little to no homology with established resistance determinants. We characterized several novel gene products, including putative enzymes that can confer high-level resistance against aminoglycosides, sulfonamides, and broad range of beta-lactams, with respect to their resistance mechanisms and clinical significance. By coupling high-resolution proteomics analysis with functional metagenomics, we discovered an unusual peptide, PPP AZI 4 , encoded within an alternative open reading frame not predicted by bioinformatics tools. Expression of the proline-rich PPP AZI 4 can promote resistance against different macrolides but not other ribosome-targeting antibiotics, implicating a new macrolidespecific resistance mechanism that could be fundamentally linked to the evolutionary design of this peptide.IMPORTANCE Antibiotic resistance is a clinical phenomenon with an evolutionary link to the microbial pangenome. Genes and protogenes encoding specialized and potential resistance mechanisms are abundant in natural environments, but understanding of their identity and genomic context remains limited. Our discovery of several previously unknown antibiotic resistance genes from uncultured soil microorganisms indicates that soil is a significant reservoir of resistance determinants, which, once acquired and "repurposed" by pathogenic bacteria, can have serious impacts on therapeutic outcomes. This study provides valuable insights into the diversity and identity of resistance within the soil microbiome. The finding of a novel peptide-mediated resistance mechanism involving an unpredicted gene product also highlights the usefulness of integrating proteomics analysis into metagenomicsdriven gene discovery.

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Section: Figmentioning

confidence: 99%

Novel Antibiotic Resistance Determinants from Agricultural Soil Exposed to Antibiotics Widely Used in Human Medicine and Animal Farming

Lau

Engelen

Gordon

et al. 2017

Appl Environ Microbiol

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“…In some Gram-positive Streptomyces species, known for their production of small-molecule antibiotics and pigments, genes for antibiotic biosynthetic enzymes are found in large clusters, which can also contain genes encoding efflux pumps and regulatory proteins that control expression of adjacent loci. Efflux pumps have been implicated in the transport of, and resistance to, antibiotics such as actinorhodin, daunorubicin, and oxytetracycline in their streptomycete producers (3)(4)(5)(6). In several cases, either the antibiotic itself, an intermediate in antibiotic synthesis, or compounds with structural similarities to the antibiotic have been demonstrated or inferred to be inducers of pump expression (3,4,7,8).…”

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confidence: 99%

The Pseudomonas aeruginosa efflux pump MexGHI-OpmD transports a natural phenazine that controls gene expression and biofilm development

Sakhtah

Koyama

Zhang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

145

159

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Redox-cycling compounds, including endogenously produced phenazine antibiotics, induce expression of the efflux pump MexGHIOpmD in the opportunistic pathogen Pseudomonas aeruginosa. Previous studies of P. aeruginosa virulence, physiology, and biofilm development have focused on the blue phenazine pyocyanin and the yellow phenazine-1-carboxylic acid (PCA). In P. aeruginosa phenazine biosynthesis, conversion of PCA to pyocyanin is presumed to proceed through the intermediate 5-methylphenazine-1-carboxylate (5-Me-PCA), a reactive compound that has eluded detection in most laboratory samples. Here, we apply electrochemical methods to directly detect 5-Me-PCA and find that it is transported by MexGHIOpmD in P. aeruginosa strain PA14 planktonic and biofilm cells. We also show that 5-Me-PCA is sufficient to fully induce MexGHI-OpmD expression and that it is required for wild-type colony biofilm morphogenesis. These physiological effects are consistent with the high redox potential of 5-Me-PCA, which distinguishes it from other well-studied P. aeruginosa phenazines. Our observations highlight the importance of this compound, which was previously overlooked due to the challenges associated with its detection, in the context of P. aeruginosa gene expression and multicellular behavior. This study constitutes a unique demonstration of efflux-based selfresistance, controlled by a simple circuit, in a Gram-negative pathogen.phenazine | RND efflux | MexGHI-OpmD | biofilm | antibiotic

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“…Liu et alidentified and isolated nine new pregnane glycosides along with six known compounds from the roots of Cynanchum auriculatum. The most abundantly known pregnane glycoside, wilfoside K1N (10) with similar structures to that of P57 isolated from Hoodia gordonii showed significant appetite suppressing effect, and further led to loss of body weight in rats (34,35). Hovenia acerba vinegar is an anti-obesity product in the market, which is known for its function to lower serum total cholesterol, plasma triglyceride levels and atherogenic index.…”

Section: Appetite Suppressantsmentioning

confidence: 99%

Anti-obesity effect of traditional Chinese medicine and natural products

Chen¹,

Lian²,

Lyu³

et al. 2016

Eur J Bio Med Res

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Abstract:As obesity has become a worldwide health problem over the past three decades, more emphasis are placed on the prevention and treatment of obesity.Research in the nutrition field has recently aroused considerable interest based on the potential of traditional Chinese medicine and natural products to counteract obesity. This review focuses on the anti-obesity action usingtraditional Chinese medicine and natural products. Some present potent anti-obesity effects because of their ability to reduce blood lipid or blood glucose while others could be used for the treatment of obesity as lipase inhibitor, lipid metabolism regulators, appetite suppressants or fatty acid synthase inhibitor. Further study should be conducted in the mechanisms and active ingredients of traditional Chinese medicine and natural products.

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

Cited by 52 publications

References 68 publications

Novel Antibiotic Resistance Determinants from Agricultural Soil Exposed to Antibiotics Widely Used in Human Medicine and Animal Farming

Novel Antibiotic Resistance Determinants from Agricultural Soil Exposed to Antibiotics Widely Used in Human Medicine and Animal Farming

The Pseudomonas aeruginosa efflux pump MexGHI-OpmD transports a natural phenazine that controls gene expression and biofilm development

Anti-obesity effect of traditional Chinese medicine and natural products

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