Cyclic AMP Regulates Bacterial Persistence through Repression of the Oxidative Stress Response and SOS-Dependent DNA Repair in Uropathogenic
            <i>Escherichia coli</i>

Molina-Quiroz, Roberto C.; Silva-Valenzuela, Cecilia A.; Brewster, Jennifer; Castro-Nallar, Eduardo; Levy, Stuart B.; Camilli, Andrew

doi:10.1128/mbio.02144-17

Cited by 70 publications

(59 citation statements)

References 55 publications

(67 reference statements)

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“…Antibiotic specificity similar to that of trkA was also found in the kdpA mutant, where we found reduced persistence to streptomycin ( Figure S2) but no change in isoniazid (Data not show). The mechanisms affected by kdpA that are involved in the generation of persister cells are specific for particular antibiotics, which has also been previously reported [62].…”

Section: Discussionsupporting

confidence: 72%

The potassium transporter KdpA affects persister formation by regulating ATP levels in Mycobacterium marinum

Liu

Wang

Yan

et al. 2020

Emerging Microbes & Infections

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Mycobacterial persistence mechanisms remain to be fully characterized. Screening a transposon insertion library of Mycobacterium marinum identified kdpA, whose inactivation reduced the fraction of persisters after exposure to rifampicin. kdpA encodes a transmembrane protein that is part of the Kdp-ATPase, an ATP-dependent high-affinity potassium (K +) transport system. We found that kdpA is induced under low K + conditions and is required for pH homeostasis and growth in media with low concentrations of K +. The inactivation of the Kdp system in a kdpA insertion mutant caused hyperpolarization of the cross-membrane potential, increased proton motive force (PMF) and elevated levels of intracellular ATP. The KdpA mutant phenotype could be complemented with a functional kdpA gene or supplementation with high K + concentrations. Taken together, our results suggest that the Kdp system is required for ATP homeostasis and persister formation. The results also confirm that ATP-mediated regulation of persister formation is a general mechanism in bacteria, and suggest that K + transporters could play a role in the regulation of ATP levels and persistence. These findings could have implications for the development of new drugs that could either target persisters or reduce their presence.

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Section: Discussionsupporting

confidence: 72%

The potassium transporter KdpA affects persister formation by regulating ATP levels in Mycobacterium marinum

Liu

Wang

Yan

et al. 2020

Emerging Microbes & Infections

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“…There are several transcriptional changes in the distinct swarm-incompatible state that are not readily explained by the ppGpp response. We anticipate that ongoing studies into the emergence of bacterial dormancy and related phenotypes (46)(47)(48)(49) in other species will help to untangle the order and hierarchy of the Ids-induced changes described here. Several candidate pathways for further analysis are apparent from the transcriptomics datasets.…”

Section: Discussionmentioning

confidence: 93%

Peer pressure from a Proteus mirabilis self-recognition system controls participation in cooperative swarm motility:

Tipping

Gibbs

2018

Preprint

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Colonies of the opportunistic pathogen Proteus mirabilis can distinguish self from non-self: in swarming colonies of two different strains, one strain excludes the other from the expanding colony edge. Predominant models characterize bacterial kin discrimination as immediate antagonism towards non-kin cells, typically through delivery of toxin effector molecules from one cell into its neighbor. Upon effector delivery, receiving cells must either neutralize it by presenting a cognate anti-toxin, as would a clonal sibling, or suffer cell death or irreversible growth inhibition, as would a non-kin cell. Here we expand this paradigm to explain the non-lethal Ids self-recognition system, which stops access to a cooperative social behavior in P. mirabilis through a distinct mechanism: selectively and transiently inducing nonself cells into a lifestyle incompatible with cooperative swarming. This state is characterized by reduced expression of genes associated with protein synthesis, virulence, and motility, and also causes non-self cells to tolerate previously lethal concentrations of antibiotics. We found that entry into this state requires a temporary activation of the stringent response in non-self cells and results in the iterative exclusion of non-self cells as a swarm colony migrates outwards. These data clarify the intricate connection between non-lethal recognition and the lifecycle of P. mirabilis swarm colonies. self recognition | Proteus mirabilis | kin selection | swarm motility | stringent response | antibiotic tolerance | bacterial communities | social evolution | cellcell communication | sociomicrobiology Correspondence: kagibbs@mcb.harvard.edu Briefly, two proteins, IdsD and IdsE, govern self iden-Tipping et al. | bioRχiv | December 9, 2018 | 1-47 2 | bioRχiv Tipping et al. | Ids controls access to swarming

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“…(p)ppGpp 0 (DrelA::FRT/DspoT::FRT) and antisense strains were constructed by recombination of PCR products and backcrossed to the wt genetic background as described (3). All mutants used in this work were subjected to whole genome sequencing and variant analyses to check for undesired off target or spontaneous mutations.…”

Section: Bacterial Strains and Growth Conditionsmentioning

confidence: 99%

The generation of persister cells is regulated at the initiation of translation by (p)ppGpp

Molina-Quiroz

Camilli

2020

Preprint

Self Cite

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Bacterial persistence is a non-heritable phenotypic trait characterized by a dormant state that leads to tolerance to different antibiotics. Several mechanisms contributing to persister cells generation have been identified. Among these, is the signaling molecule (p)ppGpp, but knowledge of how this molecule regulates persister generation is incomplete. Here, we show an increase of the persister fraction of uropathogenic Escherichia coli (UPEC) that correlates with the time of protein synthesis inhibition and a decrease in the availability of antibiotic target. Specifically, the arrest of translation initiation induces bacterial survival to ampicillin and ciprofloxacin in a (p)ppGpp-dependent manner. These findings support a global mechanism of persister cell generation and establish a regulatory role of the (p)ppGpp molecule in this phenomenon.ImportanceThe study of persister cell formation is relevant because this bacterial subpopulation is involved in the emergence of antibiotic resistance and the generation of chronic infections. A role of the (p)ppGpp molecule in the generation of the persister fraction has been described, but the identification of the regulatory mechanism mediated by this alarmone during protein translation and its contribution to persistence has not been described to date. In this work, we show that (p)ppGpp regulates the generation of persister cells at the initiation of the protein synthesis process in UPEC. Our results also suggest that a (p)ppGpp-dependent regulation of translation, might be a global mechanism for the generation of the persister fraction.

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Cyclic AMP Regulates Bacterial Persistence through Repression of the Oxidative Stress Response and SOS-Dependent DNA Repair in Uropathogenic Escherichia coli

Cited by 70 publications

References 55 publications

The potassium transporter KdpA affects persister formation by regulating ATP levels in Mycobacterium marinum

The potassium transporter KdpA affects persister formation by regulating ATP levels in Mycobacterium marinum

Peer pressure from a Proteus mirabilis self-recognition system controls participation in cooperative swarm motility:

The generation of persister cells is regulated at the initiation of translation by (p)ppGpp

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