Multiple transporters are involved in natamycin efflux in <scp><i>S</i></scp><i>treptomyces chattanoogensis</i> L10

Wang, Tanjun; Shan, Yi-Ming; Han, Li; Dou, Weiwang; Jiang, Xiaomo; Mao, Xu‐Ming; Liu, Shuiping; Guan, Wenjun; Li, Yongquan

doi:10.1111/mmi.13583

Cited by 22 publications

(17 citation statements)

References 50 publications

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“…Therefore, we speculate that SLCG_2920 might be involved in exporting lincomycin along with a transmembrane protein and thus reduce the feedback inhibition on lincomycin production inside the cell. A similar phenomenon was also detected in Streptomyces chattanoogensis, in which multiple transporters were identified to be involved in the export of natamycin (29).…”

Section: Discussionsupporting

confidence: 64%

TetR-Type Regulator SLCG_2919 Is a Negative Regulator of Lincomycin Biosynthesis in Streptomyces lincolnensis

et al. 2019

Appl Environ Microbiol

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Lincomycin A (Lin-A) is a widely used antibacterial antibiotic fermented by Streptomyces lincolnensis. However, the transcriptional regulatory mechanisms underlying lincomycin biosynthesis have seldom been investigated. Here, we first identified a TetR family transcriptional regulator (TFR), SLCG_2919, which negatively modulates lincomycin biosynthesis in S. lincolnensis LCGL. SLCG_2919 was found to specifically bind to promoter regions of the lincomycin biosynthetic gene cluster (lin cluster), including 25 structural genes, three resistance genes, and one regulatory gene, and to inhibit the transcription of these genes, demonstrating a directly regulatory role in lincomycin biosynthesis. Furthermore, we found that SLCG_2919 was not autoregulated, but directly repressed its adjacent gene, SLCG_2920, which encodes an ATP/GTP binding protein whose overexpression increased resistance against lincomycin and Lin-A yields in S. lincolnensis. The precise SLCG_2919 binding site within the promoter region of SLCG_2920 was determined by a DNase I footprinting assay and by electrophoretic mobility shift assays (EMSAs) based on base substitution mutagenesis, with the internal 10-nucleotide (nt) AT-rich sequence (AAATTATTTA) shown to be essential for SLCG_2919 binding. Our findings indicate that SLCG_2919 is a negative regulator for controlling lincomycin biosynthesis in S. lincolnensis. The present study improves our understanding of molecular regulation for lincomycin biosynthesis. IMPORTANCE TetR family transcriptional regulators (TFRs) are generally found to regulate diverse cellular processes in bacteria, especially antibiotic biosynthesis in Streptomyces species. However, knowledge of their function in lincomycin biosynthesis in S. lincolnensis remains unknown. The present study provides a new insight into the regulation of lincomycin biosynthesis through a TFR, SLCG_2919, that directly modulates lincomycin production and resistance. Intriguingly, SLCG_2919 and its adjoining gene, SLCG_2920, which encodes an ATP/GTP binding protein, were extensively distributed in diverse Streptomyces species. In addition, we revealed a new TFR binding motif, in which SLCG_2919 binds to the promoter region of SLCG_2920, dependent on the intervening AT-rich sequence rather than on the flanking inverted repeats found in the binding sites of other TFRs. These insights into transcriptional regulation of lincomycin biosynthesis by SLCG_2919 will be valuable in paving the way for genetic engineering of regulatory elements in Streptomyces species to improve antibiotic production.

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Section: Discussionsupporting

confidence: 64%

TetR-Type Regulator SLCG_2919 Is a Negative Regulator of Lincomycin Biosynthesis in Streptomyces lincolnensis

et al. 2019

Appl Environ Microbiol

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“…The three gene products of pimA, pimB, and pimH have been putatively assigned to proteins ensuring the export of pimaricin in S. natalensis. While PimA and PimB group in the family of ABC transporters, PimH might encode an efflux pump [320,324]. The functions of PimA and PimB remain to be experimentally verified.…”

Section: Pimaricin/natamycinmentioning

confidence: 99%

“…The functions of PimA and PimB remain to be experimentally verified. For the homologues of PimA and PimB (ScnA and ScnB) in S. chattanoogensis, it was reported that they are involved in primary exporters of natamycin [324]. With amino acid sequence similarities of above 95% for ScnA/ScnB and PimA/PimB, it is likely that the later enzymes have a similar function and also act as primary transporters of pimaricin.…”

Section: Pimaricin/natamycinmentioning

confidence: 99%

Actinomycete-Derived Polyketides as a Source of Antibiotics and Lead Structures for the Development of New Antimicrobial Drugs

Robertsen

Musiol-Kroll

2019

Antibiotics

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Actinomycetes are remarkable producers of compounds essential for human and veterinary medicine as well as for agriculture. The genomes of those microorganisms possess several sets of genes (biosynthetic gene cluster (BGC)) encoding pathways for the production of the valuable secondary metabolites. A significant proportion of the identified BGCs in actinomycetes encode pathways for the biosynthesis of polyketide compounds, nonribosomal peptides, or hybrid products resulting from the combination of both polyketide synthases (PKSs) and nonribosomal peptide synthetases (NRPSs). The potency of these molecules, in terms of bioactivity, was recognized in the 1940s, and started the “Golden Age” of antimicrobial drug discovery. Since then, several valuable polyketide drugs, such as erythromycin A, tylosin, monensin A, rifamycin, tetracyclines, amphotericin B, and many others were isolated from actinomycetes. This review covers the most relevant actinomycetes-derived polyketide drugs with antimicrobial activity, including anti-fungal agents. We provide an overview of the source of the compounds, structure of the molecules, the biosynthetic principle, bioactivity and mechanisms of action, and the current stage of development. This review emphasizes the importance of actinomycetes-derived antimicrobial polyketides and should serve as a “lexicon”, not only to scientists from the Natural Products field, but also to clinicians and others interested in this topic.

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“…Many other examples of ABC as well as MFS transporters used for conferring self-resistance in producer organisms to lantibiotic NAI-107, polyene macrolide natamycin, tylosin, or actinorhodin are known ( Rosteck et al, 1991 ; Xu et al, 2012 ; Mak et al, 2014 ; Pozzi et al, 2016 ; Wang et al, 2017 ). However, their molecular mechanisms and substrate specificities have not yet been elucidated.…”

Section: Self-resistance Mechanisms In Producer Organismsmentioning

confidence: 99%

Antibiotic Resistance Mechanisms in Bacteria: Relationships Between Resistance Determinants of Antibiotic Producers, Environmental Bacteria, and Clinical Pathogens

2018

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Emergence of antibiotic resistant pathogenic bacteria poses a serious public health challenge worldwide. However, antibiotic resistance genes are not confined to the clinic; instead they are widely prevalent in different bacterial populations in the environment. Therefore, to understand development of antibiotic resistance in pathogens, we need to consider important reservoirs of resistance genes, which may include determinants that confer self-resistance in antibiotic producing soil bacteria and genes encoding intrinsic resistance mechanisms present in all or most non-producer environmental bacteria. While the presence of resistance determinants in soil and environmental bacteria does not pose a threat to human health, their mobilization to new hosts and their expression under different contexts, for example their transfer to plasmids and integrons in pathogenic bacteria, can translate into a problem of huge proportions, as discussed in this review. Selective pressure brought about by human activities further results in enrichment of such determinants in bacterial populations. Thus, there is an urgent need to understand distribution of resistance determinants in bacterial populations, elucidate resistance mechanisms, and determine environmental factors that promote their dissemination. This comprehensive review describes the major known self-resistance mechanisms found in producer soil bacteria of the genus Streptomyces and explores the relationships between resistance determinants found in producer soil bacteria, non-producer environmental bacteria, and clinical isolates. Specific examples highlighting potential pathways by which pathogenic clinical isolates might acquire these resistance determinants from soil and environmental bacteria are also discussed. Overall, this article provides a conceptual framework for understanding the complexity of the problem of emergence of antibiotic resistance in the clinic. Availability of such knowledge will allow researchers to build models for dissemination of resistance genes and for developing interventions to prevent recruitment of additional or novel genes into pathogens.

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Multiple transporters are involved in natamycin efflux in Streptomyces chattanoogensis L10

Cited by 22 publications

References 50 publications

TetR-Type Regulator SLCG_2919 Is a Negative Regulator of Lincomycin Biosynthesis in Streptomyces lincolnensis

TetR-Type Regulator SLCG_2919 Is a Negative Regulator of Lincomycin Biosynthesis in Streptomyces lincolnensis

Actinomycete-Derived Polyketides as a Source of Antibiotics and Lead Structures for the Development of New Antimicrobial Drugs

Antibiotic Resistance Mechanisms in Bacteria: Relationships Between Resistance Determinants of Antibiotic Producers, Environmental Bacteria, and Clinical Pathogens

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