Negative Correlation between Lipid Content and Antibiotic Activity in Streptomyces: General Rule and Exceptions

David, Michelle; Lejeune, Clara; Abreu, Sonia; Thibessard, Annabelle; Leblond, Pierre; Chaminade, Pierre

doi:10.3390/antibiotics9060280

Cited by 7 publications

(10 citation statements)

References 49 publications

(81 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The lipid content as well as ACT production levels of the pptA mutant strain, being intermediary those of the ppk mutant and S. coelicolor , we concluded that the phosphate/energetic deficit of the pptA mutant was intermediary between that of the ppk mutant and that of S. coelicolor . These data confirmed the existence of a negative correlation between total lipid content and antibiotic production [ 5 , 24 ].…”

Section: Resultssupporting

confidence: 78%

See 1 more Smart Citation

The Phosin PptA Plays a Negative Role in the Regulation of Antibiotic Production in Streptomyces lividans

et al. 2021

Self Cite

View full text Add to dashboard Cite

In Streptomyces, antibiotic biosynthesis is triggered in phosphate limitation that is usually correlated with energetic stress. Polyphosphates constitute an important reservoir of phosphate and energy and a better understanding of their role in the regulation of antibiotic biosynthesis is of crucial importance. We previously characterized a gene, SLI_4384/ppk, encoding a polyphosphate kinase, whose disruption greatly enhanced the weak antibiotic production of Streptomyces lividans. In the condition of energetic stress, Ppk utilizes polyP as phosphate and energy donor, to generate ATP from ADP. In this paper, we established that ppk is co-transcribed with its two downstream genes, SLI_4383, encoding a phosin called PptA possessing a CHAD domain constituting a polyphosphate binding module and SLI_4382 encoding a nudix hydrolase. The expression of the ppk/pptA/SLI_4382 operon was shown to be under the positive control of the two-component system PhoR/PhoP and thus mainly expressed in condition of phosphate limitation. However, pptA and SLI_4382 can also be transcribed alone from their own promoter. The deletion of pptA resulted into earlier and stronger actinorhodin production and lower lipid content than the disruption of ppk, whereas the deletion of SLI_4382 had no obvious phenotypical consequences. The disruption of ppk was shown to have a polar effect on the expression of pptA, suggesting that the phenotype of the ppk mutant might be linked, at least in part, to the weak expression of pptA in this strain. Interestingly, the expression of phoR/phoP and that of the genes of the pho regulon involved in phosphate supply or saving were strongly up-regulated in pptA and ppk mutants, revealing that both mutants suffer from phosphate stress. Considering the presence of a polyphosphate binding module in PptA, but absence of similarities between PptA and known exo-polyphosphatases, we proposed that PptA constitutes an accessory factor for exopolyphosphatases or general phosphatases involved in the degradation of polyphosphates into phosphate.

show abstract

Section: Resultssupporting

confidence: 78%

“…Total genomic DNA extraction and transformation of E. coli and Streptomyces strains were performed according to standard procedures [ 24 ]. All the plasmids used in this study are listed in Table S2 .…”

Section: Methodsmentioning

confidence: 99%

The Phosin PptA Plays a Negative Role in the Regulation of Antibiotic Production in Streptomyces lividans

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…Since it was previously demonstrated that there is a negative correlation between total lipid content and antibiotic production in the ppk and pptA mutants of S. lividans [ 10 ], in S. coelicolor [ 5 ] as well as in other Streptomyces strains [ 11 ], we assessed the lipid content of the two strains grown on solid R2YE with no phosphate added for 72 h. The results shown in Figure 6 confirm that the total lipid content of the strain expressing the functional ATPase was significantly lower than that of the strain expressing the non-functional ATPase. These data confirmed, once again, the existence of a negative correlation between total lipid content and antibiotic production [ 5 , 6 , 11 ].…”

Section: Resultsmentioning

confidence: 99%

The Generation of an Artificial ATP Deficit Triggers Antibiotic Production in Streptomyces lividans

et al. 2022

Self Cite

View full text Add to dashboard Cite

In most Streptomyces species, antibiotic production is triggered in a condition of phosphate limitation, a condition that is known to be correlated with a low intracellular ATP content compared to growth in a condition of phosphate proficiency. This observation suggests that a low ATP content might be a direct trigger of antibiotic biosynthesis. In order to test this hypothesis, we introduced into the model strain Streptomyces lividans, a functional and a non-functional ATPase cloned into the replicative vector pOSV206 and expressed under the control of the strong ErmE* promoter. The functional ATPase was constituted by the α (AtpA), β (AtpB) and γ (AtpD) sub-units of the native F1 part of the ATP synthase of S. lividans that, when separated from the membrane-bound F0 part, bears an ATPase activity. The non-functional ATPase was a mutated version of the latter, bearing a 12 amino acids deletion encompassing the active site of the AtpD sub-unit. S. lividans was chosen to test our hypothesis since this strain hardly produces any antibiotics. However, it possesses the same biosynthetic pathways of various specialized metabolites as S. coelicolor, a phylogenetically closely related strain that produces these metabolites in abundance. Our results demonstrated that the over-expression of the functional ATPase, but not that of its mutated version, indeed correlated with the production of the bioactive metabolites of the CDA, RED and ACT clusters. These results confirmed the long known and mysterious link existing between a phosphate limitation leading to an ATP deficit and the triggering of antibiotic biosynthesis. Based on this work and the previous published results of our group, we propose an entirely novel conception of the nature of this link.

show abstract

“…Attempts were made to conjugate the plasmids pOSV10 (control) and pOSV10/DX into 19 Streptomyces strains listed in Table 2 . These strains were specifically chosen for their high total lipid content which is correlated with their low ability to produce antibiotics ( David et al, 2020 ). Of these 19 strains, 14 have an insertion site known to be identical to that of pOSV10 ( Raynal et al, 1998 ) ( Table 2 ) that was successfully conjugated into 12 of these 14 strains.…”

Section: Resultsmentioning

confidence: 99%

Metabolic adjustments in response to ATP spilling by the small DX protein in a Streptomyces strain

Apel

Levasseur²,

Lejeune³

et al. 2023

Front. Cell Dev. Biol.

Self Cite

View full text Add to dashboard Cite

ATP wasting is recognized as an efficient strategy to enhance metabolic activity and productivity of specific metabolites in several microorganisms. However, such strategy has been rarely implemented in Streptomyces species whereas antibiotic production by members of this genus is known to be triggered in condition of phosphate limitation that is correlated with a low ATP content. In consequence, to assess the effects of ATP spilling on the primary and specialized metabolisms of Streptomyces, the gene encoding the small synthetic protein DX, that has high affinity for ATP and dephosphorylates ATP into ADP, was cloned in the integrative vector pOSV10 under the control of the strong ErmE promoter. This construct and the empty vector were introduced into the species Streptomyces albogriseolus/viridodiastaticus yielding A37 and A36, respectively. A37 yielded higher biomass than A36 indicating that the DX-mediated ATP degradation resulted into a stimulation of A37 metabolism, consistently with what was reported in other microorganisms. The comparative analysis of the metabolomes of A36 and A37 revealed that A37 had a lower content in glycolytic and Tricarboxylic Acid Cycle intermediates as well as in amino acids than A36, these metabolites being consumed for biomass generation in A37. In contrast, the abundance of other molecules indicative either of energetic stress (ADP, AMP, UMP, ornithine and thymine), of activation (NAD and threonic acid) or inhibition (citramalic acid, fatty acids, TAG and L-alanine) of the oxidative metabolism, was higher in A37 than in A36. Furthermore, hydroxyl-pyrimidine derivatives and polycyclic aromatic polyketide antibiotics belonging to the angucycline class and thought to have a negative impact on respiration were also more abundantly produced by A37 than by A36. This comparative analysis thus revealed the occurrence in A37 of antagonistic metabolic strategies, namely, activation or slowing down of oxidative metabolism and respiration, to maintain the cellular energetic balance. This study thus demonstrated that DX constitutes an efficient biotechnological tool to enhance the expression of the specialized metabolic pathways present in the Streptomyces genomes that may include cryptic pathways. Its use thus might lead to the discovery of novel bioactive molecules potentially useful to human health.

show abstract

Negative Correlation between Lipid Content and Antibiotic Activity in Streptomyces: General Rule and Exceptions

Cited by 7 publications

References 49 publications

The Phosin PptA Plays a Negative Role in the Regulation of Antibiotic Production in Streptomyces lividans

The Phosin PptA Plays a Negative Role in the Regulation of Antibiotic Production in Streptomyces lividans

The Generation of an Artificial ATP Deficit Triggers Antibiotic Production in Streptomyces lividans

Metabolic adjustments in response to ATP spilling by the small DX protein in a Streptomyces strain

Contact Info

Product

Resources

About