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Eukaryotic Dna-Dependent Rna Polymerases: An Evaluation of Their Role in the Regulation of Gene Expression
Published in Gerald M. Kolodny, Eukaryotic Gene Regulation, 2018
Trevor J. C. Beebee, Peter H. W. Butterworth
There has been some further progress in the area of the eukaryotic stringent response, though the problems here are far from resolved and the mechanisms underlying the phenomenon remain elusive and controversial. Coupar et al.207 showed that in starved rats the elongation rates of template-bound polymerase I molecules were lowered substantially, but the number of enzymes bound (presumably all to ribosomal genes) were unchanged in liver nuclei. On the other hand, numbers of template-bound polymerase II molecules were reduced by more than 50% but elongation rates were unchanged. Lindell et al.208 injected rats with low concentrations of actinomycin D and showed that template-bound polymerase I and II activities in liver were much reduced 1 hr later, as was a fraction of rapidly-labeled nuclear proteins (down by 30%); this was interpreted to support the notion of a rapidly-turning-over protein factor regulating ribosomal RNA synthesis, but Iapalucci-Espinoza and Franze-Fernandez209 performed similar experiments with ascites cells and came to a different conclusion. They found that pactamycin, a translation inhibitor, reduced 45S RNA transcription more slowly than actinomycin D and thus have cast doubt on the similarity of actinomycin D effects and protein synthesis inhibitors in this regard. So there is still no consensus as to the way in which protein and ribosomal RNA synthesis are coordinated in eukaryotic cells.
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).
Biofilm and Quorum Sensing inhibitors: the road so far
Published in Expert Opinion on Therapeutic Patents, 2020
Simone Carradori, Noemi Di Giacomo, Martina Lobefalo, Grazia Luisi, Cristina Campestre, Francesca Sisto
Bacterial biofilms are ordered and structured aggregates described as ubiquitous forms of microbial communities occurring at solid-liquid, solid-air, liquid-liquid and liquid-air interfaces in different ecosystems. Their detection on mucosal linings of various organs, medical devices and wounds stimulated the researches toward these survival strategies employed by bacteria. Over 80% human infections can be related to biofilm presence [1]. They can consist of single microbial cells or co-cultures (10–15% of the total volume) embedded into a highly hydrated and self-produced exopolymeric matrix including microbial biopolymers (polysaccharides, proteins and glycoproteins, nucleic acids, lipids) as key components [2]. Polysaccharides, usually produced as structural elements of the bacterial cell wall and virulence factors, depend on the genetic profile of microorganisms involved and can be released into media (exopolysaccharides, EPS) [3]. The mechanism of resistance to antimicrobials and immune response in biofilm-related infections is different from plasmids, transposons and mutations [4], being strictly connected to (i) physical/chemical diffusion barriers for penetration; (ii) stress response activation; (iii) non-canonical growth and shape of the microorganisms; (iv) active metabolic resistance related to bacterial stringent response; and (v) emergence of new phenotypes (biofilm-related) as subpopulation of dormant cells (persisters). Genetically nonresistant planktonic cells can be killed by antibiotics, whereas when they grow up into a biofilm can be 1000 time more resistant to the same therapeutic arsenal [5].
The latest advances in β-lactam/β-lactamase inhibitor combinations for the treatment of Gram-negative bacterial infections
Published in Expert Opinion on Pharmacotherapy, 2019
Entasis Therapeutics is a pioneer in the development of antimicrobial niche therapy, their sulbactam-durlobactam (ETX2514) combination is slated to target MDR Acinetobacter spp. (Figure 2 and Table 2). This BL-BLI is in Phase 3 clinical trials for A. baumannii-calcoaceticus complex HABP, VABP, and bacteremia (clinicaltrials.gov identifier: NCT03894046). This is the only BL-BLI combination in development that demonstrates potent antimicrobial activity against Acinetobacter spp., a formidable threat to public health [85,104]. Sulbactam is traditionally known as a BLI, however due to sulbactam’s strong affinity for PBP3 in Acinetobacter spp., this BLI behaves as a BL [105]. Durlobactam inhibits class A, C, and D β-lactamases, thus is able to target the AmpC of Acinetobacter spp. (Acinetobacter-derived cephalosporinase, ADC) as well as the major groups of acquired oxacillinases (i.e., OXA-23-, OXA-24/40-, and OXA-58-families) in Acinetobacter spp [85,104]. Durlobactam also possesses β-lactam properties as it can inhibit PBP2 [85]. The sulbactam-durlobactam combination is effective in neutropenic murine thigh and lung infections models caused by MDR Acinetobacter spp. [85,104]. To identify potential resistance mechanisms to sulbactam-durlobactam, the combination and each drug alone were used to select for resistant mutants. With sulbactam, mutations in pbp3 were identified that result in amino acid substitutions to the PBP3 active site and affect sulbactam binding [106]. Moreover, alterations in the bacterial stringent response occurred, which were correlated with durlobactam exposure [106].