Cytosolic NADPH metabolism in penicillin-G producing and non-producing chemostat cultures of Penicillium chrysogenum

Kleijn, Roelco J.; Liu, Feng; Winden, Wouter A. van; Gulik, Walter M. van; Ras, Cor; Heijnen, Joseph J.

doi:10.1016/j.ymben.2006.08.004

Cited by 48 publications

(31 citation statements)

References 23 publications

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“…It contributes to ecologic fitness of the producers (1, 2) but can be metabolically costly (7). Secondary metabolism in Pseudomonas spp.…”

Section: Discussionmentioning

confidence: 99%

“…For example, a secondary metabolite with antimicrobial activity may allow organisms to inhibit competitors that occupy the same niches (6). On the other hand, secondary metabolism poses metabolic burdens to the producer by diverting precursors, cofactors, and energy from primary metabolism (7). Consequently, unnecessary expression of secondary metabolites can be costly to organisms producing secondary metabolites.…”

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confidence: 99%

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Secondary Metabolism and Interspecific Competition Affect Accumulation of Spontaneous Mutants in the GacS-GacA Regulatory System in Pseudomonas protegens

Yan

Lopes

Shaffer

et al. 2018

mBio

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Secondary metabolites are synthesized by many microorganisms and provide a fitness benefit in the presence of competitors and predators. Secondary metabolism also can be costly, as it shunts energy and intermediates from primary metabolism. In Pseudomonas spp., secondary metabolism is controlled by the GacSGacA global regulatory system. Intriguingly, spontaneous mutations in gacS or gacA (Gac Ϫ mutants) are commonly observed in laboratory cultures. Here we investigated the role of secondary metabolism in the accumulation of Gac Ϫ mutants in Pseudomonas protegens strain Pf-5. Our results showed that secondary metabolism, specifically biosynthesis of the antimicrobial compound pyoluteorin, contributes significantly to the accumulation of Gac Ϫ mutants. Pyoluteorin biosynthesis, which poses a metabolic burden on the producer cells, but not pyoluteorin itself, leads to the accumulation of the spontaneous mutants. Interspecific competition also influenced the accumulation of the Gac Ϫ mutants: a reduced proportion of Gac Ϫ mutants accumulated when P. protegens Pf-5 was cocultured with Bacillus subtilis than in pure cultures of strain Pf-5. Overall, our study associated a fitness trade-off with secondary metabolism, with metabolic costs versus competitive benefits of production influencing the evolution of P. protegens, assessed by the accumulation of Gac Ϫ mutants.IMPORTANCE Many microorganisms produce antibiotics, which contribute to ecologic fitness in natural environments where microbes constantly compete for resources with other organisms. However, biosynthesis of antibiotics is costly due to the metabolic burdens of the antibiotic-producing microorganism. Our results provide an example of the fitness trade-off associated with antibiotic production. Under noncompetitive conditions, antibiotic biosynthesis led to accumulation of spontaneous mutants lacking a master regulator of antibiotic production. However, relatively few of these spontaneous mutants accumulated when a competitor was present. Results from this work provide information on the evolution of antibiotic biosynthesis and provide a framework for their discovery and regulation.KEYWORDS interspecific competition, Pseudomonas, secondary metabolism, spontaneous mutations, GacS-GacA S econdary metabolites play important roles in physiological adaptation and ecologic fitness of the organisms producing secondary metabolites (1, 2). These metabolites vary widely in structure and biological activity, with some having valuable pharmaceu-

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“…It contributes to ecologic fitness of the producers (1, 2) but can be metabolically costly (7). Secondary metabolism in Pseudomonas spp.…”

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Secondary Metabolism and Interspecific Competition Affect Accumulation of Spontaneous Mutants in the GacS-GacA Regulatory System in Pseudomonas protegens

Yan

Lopes

Shaffer

et al. 2018

mBio

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“…Several biological reasons may explain this complex regulation. Active synthesis of antibiotics represents a metabolic burden for the producing organisms, which draws heavily on the precursor, ATP, and electron carrier pools from primary metabolism (13). The latter suggests that, in natural environment, antibiotics are synthesized only when they provide a survival benefit.…”

Section: Regulation Of Antibiotic Biosynthesis and Mechanisms Of Selfmentioning

confidence: 99%

Antibiotics

Zotchev

2012

Natural Products in Chemical Biology

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“…As Kleijn et al [103] have argued classical strain improvement strategies based on increasing the levels of enzymes in secondary metabolic pathways ''will, at some point, lead to shift of the metabolic bottleneck from secondary metabolism towards primary metabolism''. These authors examined the synthesis of penicillin G by Penicillium chrysogenum in carbonlimited chemostat cultures in order to test the hypothesis that the supply of NADPH (critical for the biosynthesis of b-lactam amino acid precursors such as cysteine) is principally through the oxidative branch of the pentose phosphate pathway (PPP).…”

Section: Industrial Applicationsmentioning

confidence: 99%

The renaissance of continuous culture in the post-genomics age

Bull

2010

J Ind Microbiol Biotechnol

108

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The development of continuous culture techniques 60 years ago and the subsequent formulation of theory and the diversification of experimental systems revolutionised microbiology and heralded a unique period of innovative research. Then, progressively, molecular biology and thence genomics and related high-information-density omics technologies took centre stage and microbial growth physiology in general faded from educational programmes and research funding priorities alike. However, there has been a gathering appreciation over the past decade that if the claims of systems biology are going to be realised, they will have to be based on rigorously controlled and reproducible microbial and cell growth platforms. This revival of continuous culture will be long lasting because its recognition as the growth system of choice is firmly established. The purpose of this review, therefore, is to remind microbiologists, particularly those new to continuous culture approaches, of the legacy of what I call the first age of continuous culture, and to explore a selection of researches that are using these techniques in this post-genomics age. The review looks at the impact of continuous culture across a comprehensive range of microbiological research and development. The ability to establish (quasi-) steady state conditions is a frequently stated advantage of continuous cultures thereby allowing environmental parameters to be manipulated without causing concomitant changes in the specific growth rate. However, the use of continuous cultures also enables the critical study of specified transition states and chemical, physical or biological perturbations. Such dynamic analyses enhance our understanding of microbial ecology and microbial pathology for example, and offer a wider scope for innovative drug discovery; they also can inform the optimization of batch and fed-batch operations that are characterized by sequential transitions states.

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Cytosolic NADPH metabolism in penicillin-G producing and non-producing chemostat cultures of Penicillium chrysogenum

Cited by 48 publications

References 23 publications

Secondary Metabolism and Interspecific Competition Affect Accumulation of Spontaneous Mutants in the GacS-GacA Regulatory System in Pseudomonas protegens

Secondary Metabolism and Interspecific Competition Affect Accumulation of Spontaneous Mutants in the GacS-GacA Regulatory System in Pseudomonas protegens

Antibiotics

The renaissance of continuous culture in the post-genomics age

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