The expression of antibiotic resistance genes in antibiotic‐producing bacteria

Mak, Stefanie; Xu, Ye; Nodwell, Justin R.

doi:10.1111/mmi.12689

Cited by 72 publications

(59 citation statements)

References 59 publications

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“…Interestingly, the gene required for production of 5-Me-PCA from PCA, phzM, is located next to the mex operon on the P. aeruginosa chromosome (Fig. 1A) an arrangement that is common for genes encoding (i) efflux pumps and (ii) biosynthetic enzymes that generate efflux pump substrates (8). This genetic organization prompts the hypothesis that 5-Me-PCA is the natural substrate of MexGHI-OpmD.…”

mentioning

confidence: 98%

“…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%

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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.

148

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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mentioning

confidence: 98%

mentioning

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.

148

159

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“…Through selection and exchange of genetic resistant elements, antibiotics boost the emergence of multi-drug resistant strains. Bacteria which are sensitive to the antibiotics are suppressed or killed, while resistant strains survive and may become endemic and burst out in the hospital (8,9). Based on previous research, the major mechanisms of antibiotic resistance include extended spectrum β-lactamases (ESBLs), AmpC β-lactamases, carbapenemases, staphylococcal cassette chromosome mec (SCCmec), VanA ligase, porin deficiency, and active efflux pumps ( Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Nosocomial infection and its molecular mechanisms of antibiotic resistance

Xia

Gao

Tang

2016

BST

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“…'Antibiotics' should be regarded as serious candidates. Antibiotic resistance is indeed mandatory for antibiotic makers such as streptomycetes, which infers that their 'weapons' against competitors are also active against the producing species (16)(17)(18)(19)(20)(21). To survive production of their natural products, Streptomyces possess self-defense mechanisms identical to those developed and acquired by human and animal pathogens (22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

Prodiginine Production inStreptomyces coelicolorCorrelates Temporally and Spatially to Programmed Cell Death

Tenconi

Traxler

Hoebreck

et al. 2018

Preprint

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Programmed cell death (PCD) is a common feature of multicellularity and morphogenesis in bacteria. While cell death has been well documented when Streptomyces species switch from vegetative (nutrition) to aerial (reproduction) growth, lethal determinants are yet to be discovered to unveil the genetic basis of PCD in mycelial bacteria. In this work we used prodiginines of Streptomyces coelicolor as model to test the hypothesis that a bacterium uses 'self-made' antiproliferative DNA-damaging agents as toxins of their PCD process. Spatiotemporal visualisation of the autofluorescence of prodiginines reveals that their biosynthesis is triggered in the dying zone of the colony prior to morphological differentiation of the mycelium.A prodiginine nonproducer showed hyper-accumulation of viable filaments, with increased RNA and proteins synthesis when most of the mycelium of the wild-type strain was dead when prodiginine accumulated. Addition of a prodiginine synthesis inhibitor also strongly favoured viable over dead filaments. As self-toxicity has also been reported for other producers of DNAdamaging agents we propose that cytotoxic metabolites synthetized during the morphological transition of filamentous bacteria may be used to execute PCD. Significance StatementActinobacteria are prolific producers of compounds with antiproliferative activity, but why these bacteria synthetize metabolites with this bioactivity has so far remained a mystery. Using prodiginines (PdGs) as model system, we revealed that the spatio-temporal synthesis of these molecules correlates to cell death of the producer Streptomyces coelicolor and that inhibition of their synthesis results in hyper-accumulation of viable filaments. Since PdGs potentiate death of S. coelicolor recurrently prior to morphological differentiation, this is a form of programmed cell death (PCD). Hence, next to weapons in competition between organisms or signals in interand intra-species communications, we propose a third role for secondary metabolites i.e., elements required for self-toxicity in PCD processes.

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The expression of antibiotic resistance genes in antibiotic‐producing bacteria

Cited by 72 publications

References 59 publications

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

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

Nosocomial infection and its molecular mechanisms of antibiotic resistance

Prodiginine Production inStreptomyces coelicolorCorrelates Temporally and Spatially to Programmed Cell Death

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