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Lethal Consequences of Overcoming Metabolic Restrictions Imposed on a Cooperative Bacterial Population.

ABSTRACT: Quorum sensing (QS) controls cooperative activities in many Proteobacteria In some species, QS-dependent specific metabolism contributes to the stability of the cooperation. However, the mechanism by which QS and metabolic networks have coevolved to support stable public good cooperation and maintenance of the cooperative group remains unknown. Here we explored the underlying mechanisms of QS-controlled central metabolism in the evolutionary aspects of cooperation. In Burkholderia glumae, the QS-dependent glyoxylate cycle plays an important role in cooperativity. A bifunctional QS-dependent transcriptional regulator, QsmR, rewired central metabolism to utilize the glyoxylate cycle rather than the tricarboxylic acid cycle. Defects in the glyoxylate cycle caused metabolic imbalance and triggered high expression of the stress-responsive chaperonin GroEL. High-level expression of GroEL in glyoxylate cycle mutants interfered with the biosynthesis of a public resource, oxalate, by physically interrupting the oxalate biosynthetic enzyme ObcA. Under such destabilized cooperativity conditions, spontaneous mutations in the qsmR gene in glyoxylate cycle mutants occurred to relieve metabolic stresses, but these mutants lost QsmR-mediated pleiotropy. Overcoming the metabolic restrictions imposed on the population of cooperators among glyoxylate cycle mutants resulted in the occurrence and selection of spontaneous qsmR mutants despite the loss of other important functions. These results provide insight into how QS bacteria have evolved to maintain stable cooperation via QS-mediated metabolic coordination.IMPORTANCE We address how quorum sensing (QS) has coevolved with metabolic networks to maintain bacterial sociality. We found that QS-mediated metabolic rewiring is critical for sustainable bacterial cooperation in Burkholderia glumae The loss of the glyoxylate cycle triggered the expression of the stress-responsive molecular chaperonin GroEL. Excessive biosynthesis of GroEL physically hampered biosynthesis of a public good, oxalate. This is one good example of how molecular chaperones play critical roles in bacterial cooperation. In addition, we showed that metabolic restrictions in the glyoxylate cycle acted as a selection pressure on metabolic networks; there were spontaneous mutations in the qsmR gene to relieve such stresses. However, the presence of spontaneous qsmR mutants had tragic consequences for a cooperative population of B. glumae due to failure of qsmR-dependent activation of public good biosynthesis. These results provide a good example of a bacterial strategy for robust cooperation via QS-mediated metabolic rewiring.

SUBMITTER: Goo E

PROVIDER: S-EPMC5347341 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Lethal Consequences of Overcoming Metabolic Restrictions Imposed on a Cooperative Bacterial Population.

Goo Eunhye E Kang Yongsung Y Lim Jae Yun JY Ham Hyeonheui H Hwang Ingyu I

mBio 20170228 1

Quorum sensing (QS) controls cooperative activities in many <i>Proteobacteria</i> In some species, QS-dependent specific metabolism contributes to the stability of the cooperation. However, the mechanism by which QS and metabolic networks have coevolved to support stable public good cooperation and maintenance of the cooperative group remains unknown. Here we explored the underlying mechanisms of QS-controlled central metabolism in the evolutionary aspects of cooperation. In <i>Burkholderia glum ...[more]

PMID: 28246357

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Project description:The social environment in which individuals live affects their fitness and in turn population dynamics as a whole. Birds with facultative cooperative breeding can live in social groups with dominants, subordinate helpers that assist with the breeding of others, and subordinate non-helpers. Helping behaviour benefits dominants through increased reproductive rates and reduced extrinsic mortality, such that cooperative breeding might have evolved in response to unpredictable, harsh conditions affecting reproduction and/or survival of the dominants. Additionally, there may be different costs and benefits to both helpers and non-helpers, depending on the time-scale. For example, early-life costs might be compensated by later-life benefits. These differential effects are rarely analysed in the same study. We examined whether helping behaviour affects population persistence in a stochastic environment and whether there are direct fitness consequences of different life-history tactics adopted by helpers and non-helpers. We parameterised a matrix population model describing the population dynamics of female Seychelles warblers Acrocephalus sechellensis, birds that display facultative cooperative breeding. The stochastic density-dependent model is defined by a (st)age structure that includes life-history differences between helpers and non-helpers and thus can estimate the demographic mechanisms of direct benefits of helping behaviour. We found that population dynamics are strongly influenced by stochastic variation in the reproductive rates of the dominants, that helping behaviour promotes population persistence and that there are only early-life differences in the direct fitness of helpers and non-helpers. Through a matrix population model, we captured multiple demographic rates simultaneously and analysed their relative importance in determining population dynamics of these cooperative breeders. Disentangling early-life versus lifetime effects of individual tactics sheds new light on the costs and benefits of helping behaviour. For example, the finding that helpers and non-helpers have similar lifetime reproductive outputs and that differences in reproductive values between the two life-history tactics arise only in early life suggests that overall, helpers and non-helpers have a similar balance of costs and benefits when analysing direct benefits. We recommend analysing the consequence of different life-history tactics, during both early life and over the lifetime, as analyses of these different time frames may produce conflicting results.

Project description:BackgroundBetween August 2016 and July 2018, three states classified gabapentin as a Schedule V drug and nine states implemented prescription drug monitoring program (PDMP) regulation for gabapentin. It is highly unusual for states to take drug regulation into their own hands. The impact of these changes on gabapentin prescribing is unclear.ObjectiveTo determine the effect of state-imposed regulation on gabapentin prescribing for Medicare Part D enrollees from 2013 to 2018.DesignPopulation-based difference-in-difference(DID) analysis study utilizing the Medicare Part D Prescriber Public Use File.ParticipantsAll eligible Medicare Part D prescribers excluding those outside of the fifty states and the District of Columbia were included in our analysis. Prescriber data and key sociodemographic variables were organized by state and year. States with a gabapentin schedule change or PDMP regulation enacted before 2019 were included in the intervention group. For the Schedule V DID analysis, a control group of the ten highest opioid-prescribing states was used.InterventionsStates with gabapentin schedule changes or PDMP regulation before January 1, 2019, were included and compared to control states that did not implement these policies.Main measuresTotal days' supply of gabapentin per enrollee per year was the primary outcome variable.Key resultsThe mean total days' supply of gabapentin per enrollee increased 41% from 19.71 to 27.81 total days' supply per enrollee per year between 2013 and 2018. After adjustment, Schedule V gabapentin regulation resulted in a reduction of 8.37 total days of gabapentin prescribed per enrollee (95% confidence interval of - 10.34 to - 6.39). In contrast, PDMP regulation resulted in a reduction of 1.01 total days of gabapentin prescribed per enrollee (95% confidence interval of - 1.74 to - 0.29).ConclusionsClassifying gabapentin as a Schedule V drug results in substantial reduction in total days prescribed whereas PDMP regulation results in modest reduction.

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Lethal Consequences of Overcoming Metabolic Restrictions Imposed on a Cooperative Bacterial Population.

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Lethal Consequences of Overcoming Metabolic Restrictions Imposed on a Cooperative Bacterial Population.

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