ABC transporter genes from Streptomyces ghanaensis moenomycin biosynthetic gene cluster: roles in antibiotic production and export

Ostash, Bohdan; Doud, Emma H.; Walker, Suzanne

doi:10.1007/s00203-012-0827-9

Cited by 14 publications

(13 citation statements)

References 31 publications

(38 reference statements)

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“…One effective way is to pump the antibiotic out of the cells. This process requires the participation of transporters encoded in the antibiotic biosynthetic gene clusters (29,30). Since the biosynthesis of antibiotics is subject to complex cascade regulation, it is reasonable to expect that the export process is also under the control of regulators.…”

Section: Discussionmentioning

confidence: 99%

GouR, a TetR Family Transcriptional Regulator, Coordinates the Biosynthesis and Export of Gougerotin in Streptomyces graminearus

Wei

Tian

Niu

et al. 2014

Appl Environ Microbiol

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Gougerotin is a peptidyl nucleoside antibiotic. It functions as a specific inhibitor of protein synthesis by binding ribosomal peptidyl transferase and exhibits a broad spectrum of biological activities. gouR, situated in the gougerotin biosynthetic gene cluster, encodes a TetR family transcriptional regulatory protein. Gene disruption and genetic complementation revealed that gouR plays an important role in the biosynthesis of gougerotin. Transcriptional analysis suggested that GouR represses the transcription of the gouL-to-gouB operon consisting of 11 structural genes and activates the transcription of the major facilitator superfamily (MFS) transporter gene (gouM). Electrophoresis mobility shift assays (EMSAs) and DNase I footprinting experiments showed that GouR has specific DNA-binding activity for the promoter regions of gouL, gouM, and gouR. Our data suggested that GouR modulates gougerotin production by coordinating its biosynthesis and export in Streptomyces graminearus.

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Section: Discussionmentioning

confidence: 99%

GouR, a TetR Family Transcriptional Regulator, Coordinates the Biosynthesis and Export of Gougerotin in Streptomyces graminearus

Wei

Tian

Niu

et al. 2014

Appl Environ Microbiol

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“…All constructs were transferred into Streptomyces conjugally. The presence and stability of inheritance of φ C31-based constructs in streptomycetes was checked as described earlier [63,64]. …”

Section: Methodsmentioning

confidence: 99%

Pleiotropic regulatory genes bldA , adpA and absB are implicated in production of phosphoglycolipid antibiotic moenomycin

et al. 2013

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Unlike the majority of actinomycete secondary metabolic pathways, the biosynthesis of peptidoglycan glycosyltransferase inhibitor moenomycin in Streptomyces ghanaensis does not involve any cluster-situated regulators (CSRs). This raises questions about the regulatory signals that initiate and sustain moenomycin production. We now show that three pleiotropic regulatory genes for Streptomyces morphogenesis and antibiotic production—bldA, adpA and absB—exert multi-layered control over moenomycin biosynthesis in native and heterologous producers. The bldA gene for tRNALeuUAA is required for the translation of rare UUA codons within two key moenomycin biosynthetic genes (moe), moeO5 and moeE5. It also indirectly influences moenomycin production by controlling the translation of the UUA-containing adpA and, probably, other as-yet-unknown repressor gene(s). AdpA binds key moe promoters and activates them. Furthermore, AdpA interacts with the bldA promoter, thus impacting translation of bldA-dependent mRNAs—that of adpA and several moe genes. Both adpA expression and moenomycin production are increased in an absB-deficient background, most probably because AbsB normally limits adpA mRNA abundance through ribonucleolytic cleavage. Our work highlights an underappreciated strategy for secondary metabolism regulation, in which the interaction between structural genes and pleiotropic regulators is not mediated by CSRs. This strategy might be relevant for a growing number of CSR-free gene clusters unearthed during actinomycete genome mining.

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“…Notably, among the cellenvelope-active agents tested, moenomycin A was consistently affected by abcA expression, whereas ␤-lactams were variably affected in MSSA and MRSA backgrounds. Moenomycin A, which is a natural hydrophobic antibiotic that inhibits the glycosyltransferase domain of penicillin-binding proteins (PBPs) (41), is known to be a substrate of ATP-dependent transporters in other species. In Streptomyces ghanaensis, the genes moeD5moeJ5 and moeX5moeP5, which are highly similar to abc transporter genes, are involved in the export of moenomycin A (41).…”

Section: Discussionmentioning

confidence: 99%

“…Moenomycin A, which is a natural hydrophobic antibiotic that inhibits the glycosyltransferase domain of penicillin-binding proteins (PBPs) (41), is known to be a substrate of ATP-dependent transporters in other species. In Streptomyces ghanaensis, the genes moeD5moeJ5 and moeX5moeP5, which are highly similar to abc transporter genes, are involved in the export of moenomycin A (41). We have now shown that in an MSSA background there is a 100-fold increase in the MIC of moenomycin A with overexpression of abcA and a 10-fold effect in the MRSA background.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Expression of abcA and Its Response to Environmental Conditions

et al. 2014

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The ATP-dependent transporter gene abcA in Staphylococcus aureus confers resistance to hydrophobic ␤-lactams. In strain ISP794, abcA is regulated by the transcriptional regulators MgrA and NorG and shares a 420-nucleotide intercistronic region with the divergently transcribed pbp4 gene, which encodes the transpeptidase Pbp4. Exposure of exponentially growing cells to iron-limited media, oxidative stress, and acidic pH (5.5) for 0.5 to 2 h had no effect on abcA expression. In contrast, nutrient limitation produced a significant increase in abcA transcripts. We identified three additional regulators (SarA, SarZ, and Rot) that bind to the overlapping promoter region of abcA and pbp4 in strain MW2 and investigated their role in the regulation of abcA expression. Expression of abcA is decreased by 10.0-fold in vivo in a subcutaneous abscess model. In vitro, abcA expression depends on rot and sarZ regulators. Moenomycin A exposure of strain MW2 produced an increase in abcA transcripts. Relative to MW2, the MIC of moenomycin was decreased 8-fold for MW2⌬abcA and increased 10-fold for the MW2 abcA overexpresser, suggesting that moenomycin is a substrate of AbcA.

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ABC transporter genes from Streptomyces ghanaensis moenomycin biosynthetic gene cluster: roles in antibiotic production and export

Cited by 14 publications

References 31 publications

GouR, a TetR Family Transcriptional Regulator, Coordinates the Biosynthesis and Export of Gougerotin in Streptomyces graminearus

GouR, a TetR Family Transcriptional Regulator, Coordinates the Biosynthesis and Export of Gougerotin in Streptomyces graminearus

Pleiotropic regulatory genes bldA , adpA and absB are implicated in production of phosphoglycolipid antibiotic moenomycin

Regulation of Expression of abcA and Its Response to Environmental Conditions

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