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Hormesis
Published in T. D. Luckey, Radiation Hormesis, 2020
An attractive generalization suggests that unusual cell reactions arise following cell stress from radiation, oxidations, oncogenic viruses, heat, and a wide variety of chemical poisons.473,801 This oxidation stress leads to the production and accumulation of hyperphosphorylated nucleotides, e.g., adenine-P-P-P-P-adenine (AppppA). Such compounds, called “alarmones”, are produced in large quantities by “heat shock” proteins.801 Production of these proteins may be a cell response to general stress. The alarmones alert cells to the onset of the need for drastically changed priorities. The modified cell, or organism, becomes more resistant to harm from many agents.
Biofilm Persisters
Published in Chaminda Jayampath Seneviratne, Microbial Biofilms, 2017
Peng Li, Chaminda Jayampath Seneviratne, Lijian Jin
Biofilms demonstrate extensive structural, chemical and biological heterogeneity, containing cells in various physiological states. In response to local environmental conditions, biofilms enrich differentiation of specific phenotypes with increased adaptability [43]. In biofilms, cells within the internal regions often encounter limited access to nutrients and enter into a dormant state [44]. In addition, bacteria trigger a stringent response that promotes cell survival under nutrient-limited conditions. This response is coordinated by RelA- and SpoT-mediated synthesis of the alarmone guanosine tetraphosphate (ppGpp) that massively reprogrammes gene expression via direct interaction with RNA polymerase or indirect σ-factor competition [45]. Indeed, antibiotic tolerance of bacterial biofilm persisters has been closely linked to TA operons, dormancy and stringent response. It has been reported that overexpression of the TA gene yafQ induces multidrug tolerance in E. coli biofilms, and disruption of yafQ reduces the level of persisters in the biofilms, but not in stationary-phase planktonic cells [46]. Inactivation of this stringent response by deletion of RelA and SpoT in P. aeruginosa resulted in a dramatic decrease of persistence in stationary phase and biofilms, and the reduced susceptibility was restored via complementation of the two genes [18]. The requirement of ppGpp for persistence has also been observed in E. coli biofilms, and it is demonstrated that ppGpp induces slow growth and antibiotic tolerance via activation of TA systems through inorganic polyphosphate- and Lon protease-dependent degradation of antitoxins [47].
Mycobacterial biofilms as players in human infections: a review
Published in Biofouling, 2021
Esmeralda Ivonne Niño-Padilla, Carlos Velazquez, Adriana Garibay-Escobar
Bacteria are also protected against environmental stress by a stringent response mediated by the hyperphosphorylated guanine nucleotides ppGpp and pppGpp, together known as (p)ppGpp (alarmone) (Gupta et al. 2015). (p)ppGpp is produced by the hydrolysis of c-di-GMP with HD-GYP PDE activity or through the transfer of pyrophosphate from ATP to GDP in a process mediated by Rel, an alarmone synthetase/hydrolase enzyme that also exhibits catalytic activity on (p)ppGpp to obtain GDP or GTP in return (Polkade et al. 2016; Prusa et al. 2018). The effect of knocking out one of Rel’s domains has been demonstrated, in which its synthetase activity was considered necessary for persistence during chronic infection and its hydrolase activity compromised M. tuberculosis survival in both acute and chronic stages, whereas the lack of the whole enzyme caused defective pellicles and biofilms (Weiss and Stallings 2013). Furthermore, its absence was found to limit the ability of mycobacteria to enter into a dormant state and weakened it against isoniazid treatment in infected mice (Dutta et al. 2019). Consistent with this finding, Rel was found to be involved in lung tubercle lesions, caseous granulomas, and dissemination in guinea pigs, a more accurate model for studying chronic TB infections (Klinkenberg et al. 2010).
Regulatory mechanisms of exopolysaccharide synthesis and biofilm formation in Streptococcus mutans
Published in Journal of Oral Microbiology, 2023
Ting Zheng, Meiling Jing, Tao Gong, Jiangchuan Yan, Xiaowan Wang, Mai Xu, Xuedong Zhou, Jumei Zeng, Yuqing Li
Second messenger c-di-AMP and Ap4A regulate S. mutans biofilms formation. Inhibitors targeting synthetase/hydrolase or receptor proteins can affect the intracellular levels or signaling transduction of second messengers and inhibit biofilm formation. Currently, most c-di-AMP inhibitors target PDE and DisA [126]. For example, three inhibitors of Bacillus subtilis DisA, bromophenol-TH, suramin, and the tea polyphenol theaflavin digallate, were identified [126]. Stress alarmone ppGpp could competitively inhibit B. subtilis GdpP (PDE) [127]. However, inhibitors targeting S. mutans DAC/PDE still need further investigation. The mechanisms of action of these inhibitors and whether there might be an impact on the other flora in the oral cavity are still unclear.
Biofilm-related disease
Published in Expert Review of Anti-infective Therapy, 2018
The alarmone, ppGpp, is almost ubiquitous in the bacterial domain and plays a central role in environmentally-induced persister cell formation. It was discovered as the effector molecule of the stringent response that is activated in almost all bacteria by a host of different environmental stresses. In addition to the stringent response, activation of the bacterial SOS response, a signaling pathway that upregulates DNA repair functions, appears to be associated with bacterial persistence. Having shown that the stringent response is central to persister induction and virulence, it is conceivable that inhibitors of the stringent response could have therapeutic potential [94].