Expression of genes of the Pho regulon is altered in Streptomyces coelicolor

Abstract

Most currently used antibiotics originate from Streptomycetes and phosphate limitation is an important trigger of their biosynthesis. Understanding the molecular processes underpinning such regulation is of crucial importance to exploit the great metabolic diversity of these bacteria and get a better understanding of the role of these molecules in the physiology of the producing bacteria. To contribute to this field, a comparative proteomic analysis of two closely related model strains, Streptomyces lividans and Streptomyces coelicolor was carried out. These strains possess identical biosynthetic pathways directing the synthesis of three well-characterized antibiotics (CDA, RED and ACT) but only S. coelicolor expresses them at a high level. Previous studies established that the antibiotic producer, S. coelicolor, is characterized by an oxidative metabolism and a reduced triacylglycerol content compared to the none producer, S. lividans, characterized by a glycolytic metabolism. Our proteomic data support these findings and reveal that these drastically different metabolic features could, at least in part, due to the weaker abundance of proteins of the two component system PhoR/PhoP in S. coelicolor compared to S. lividans. In condition of phosphate limitation, PhoR/PhoP is known to control positively and negatively, respectively, phosphate and nitrogen assimilation and our study revealed that it might also control the expression of some genes of central carbon metabolism. The tuning down of the regulatory role of PhoR/PhoP in S. coelicolor is thus expected to be correlated with low and high phosphate and nitrogen availability, respectively and with changes in central carbon metabolic features. These changes are likely to be responsible for the observed differences between S. coelicolor and S. lividans concerning energetic metabolism, triacylglycerol biosynthesis and antibiotic production. Furthermore, a novel view of the contribution of the bio-active molecules produced in this context, to the regulation of the energetic metabolism of the producing bacteria, is proposed and discussed.

A Genome-Scale Insight into the Effect of Shear Stress During the Fed-Batch Production of Clavulanic Acid by Streptomyces Clavuligerus

“…This response is controlled by the two-component system PhoR/PhoP, which is able to induce the high-affinity phosphate transport system, phosphatases, down-regulation of phosphate consuming processes and upregulation of genes involving phosphate mediated reactions [ 53 , 54 ]. In phosphate limited conditions, the homeostatic processes triggered to compensate the ATP deficit, lead to a strong activation of the oxidative and amino acids metabolism, resulting in abundant generation of reduced cofactors and ATP, favoring the antibiotic synthesis as a feasible mechanism to adjust the ATP generation to low phosphate availability [ 55 , 56 ]. Additionally, penicillin and cephalosporin antibiotics induce an ATP-consuming futile cycle of polymerization/degradation of the cell wall, regulating the ATP levels and phosphate content [ 52 , 57 ].…”

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

“…It also revealed that some strains have far lower lipid content on glucose than on glycerol ( Figure 1b). These strains might have, like S. coelicolor, an oxidative metabolism yielding an insufficient amount of glycerol3P to support high lipid biosynthesis on glucose [9]. Thirty and fifteen strains (forty-five strains) had a medium (50-100 µg/mg) or high (>100 µg/mg) lipid content on glycerol whereas only twenty and seven strains (twenty-seven strains) had medium or high lipid content on glucose, respectively.…”

“…S. coelicolor suffers energetic stress since the two component system PhoR/PhoP that positively controls the phosphate supply, necessary for ATP synthesis, is weakly expressed in this strain [9] whereas the ppk mutant suffers energetic stress since its lacks PPK, an important enzyme that regenerates ATP from ADP and polyphosphate [10,11]. In these two strains, similar homeostatic processes are triggered to restore their energetic balance [7,9]. Such processes include the activation of their TCA cycle, which yields reduced co-factors whose re-oxidation by the respiratory chain generates ATP.…”

“…Such processes include the activation of their TCA cycle, which yields reduced co-factors whose re-oxidation by the respiratory chain generates ATP. In these strains, with acetylCoA being used to feed the TCA cycle, it is not available to be stored as lipids [7,9]. The activation of the oxidative metabolism of these strains was shown to be correlated with the production of the antibiotics CDA (calcium dependent antibiotic), RED (undecylprodigiosin) and ACT (actinorhoddin) [7].…”

Clavulanic Acid Production by Streptomyces clavuligerus: Insights from Systems Biology, Strain Engineering, and Downstream Processing

“…CA biosynthesis is induced during phosphate limited conditions; recently it has been proposed that CA production may be a consequence of a homeostatic response aimed to compensate for the ATP deficit under phosphate depletion [ 19 ]. This mechanism would trigger a strong activation of oxidative and amino acid metabolism, producing reduced cofactors and ATP and favoring the antibiotic biosynthesis as a feasible mechanism to adjust the ATP generation [ 20 , 21 ]. Moreover, the simultaneous secretion of penicillin and cephalosporins antibiotics along with β-lactamase enzymes and β-lactamase inhibitors would tightly control the energetic impact of an ATP-consuming futile cycle of polymerization/degradation of the cell wall caused by the β-lactam antibiotics accumulation [ 19 , 22 , 23 ].…”