Nucleotide biosynthesis: the base of bacterial pathogenesis

Goncheva, Mariya I.; Chin, Denny; Heinrichs, David E.

doi:10.1016/j.tim.2021.12.007

Cited by 51 publications

(40 citation statements)

References 62 publications

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“…This result is consistent with the ubiquitous role of nucleotide metabolism across bacterial species 31 . Additionally, it has been shown that the nucleotide metabolism pathway plays a role in pathogenesis, further providing evidence that the GENREs in PATHGENN accurately capture and represent the biochemical processes in pathobionts 32 . Furthermore, there was an enrichment of xenobiotic metabolic subsystems in unique reactions (7% more).…”

Section: Discussionmentioning

confidence: 97%

Evolution shapes metabolic function and niche-specific antimicrobial targets in pathobionts

Glass

Dillard

Warren

et al. 2022

Preprint

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Pathogens pose a major risk to human health globally, causing 44% of deaths in low-resource countries. Currently, there are over 500 known bacterial pathobionts, covering a wide range of functional capabilities. Some well-known pathobionts are well characterized computationally and experimentally. However, to gain a deeper understanding of how pathobionts are evolutionarily related to the principles that govern their different functions and ultimately identify possible targeted antimicrobials, we must consider both well-known and lesser-known pathobionts. Here, we developed a database of genome-scale metabolic network reconstructions (GENREs) called PATHGENN, which contains 914 models of pathobiont metabolism to address these questions related to functional metabolic evolution and adaptation. We determined the metabolic phenotypes across all known pathobionts and the role of isolate environment in functional metabolic adaptation. We also predicted novel antimicrobial targets for bacteria specific to their physiological niche. Understanding the functional metabolic similarities between pathobionts is the first step to ultimately developing a precision medicine framework for addressing all infections.

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Section: Discussionmentioning

confidence: 97%

Evolution shapes metabolic function and niche-specific antimicrobial targets in pathobionts

Glass

Dillard

Warren

et al. 2022

Preprint

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“…Therapeutic targeting of proteins involved in these processes is theoretically possible, but at present is not clear. At the same time, nucleoside analogs are common drugs in other nonbacterial diseases, and evaluation of their possible role as antibacterial drugs may open new opportunities [60]. So antimycotic drug 5-fluorocytosine was able to suppress virulence of P. aeruginosa in a murine model of lung infection [61].…”

Section: Discussionmentioning

confidence: 99%

Biofilm matrix proteome of clinical strain of P. aeruginosa

Егорова¹,

Solovyev²,

Polyakov³

et al. 2021

Preprint

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Extracellular matrix plays a pivotal role in biofilm biology. Despite importance of matrix proteins as potential targets for development of antibacterial therapeutics little is known about matrix proteomes. While P. aeruginosa is one of the most important pathogens with emerging antibiotic resistance only few studies are devoted to matrix proteomes and there are no studies describing matrix proteome for any clinical isolates. As matrix responsible for some extracellular functions, it is expected that protein composition should be different in comparison with embedded in biofilm cells and this difference reflects possible active processes in matrix. Here we report the first matrix proteome for clinical isolate of P. aeruginosa in comparison with embedded cells. We have identified the largest number of proteins in matrix among all published studies. Ten proteins were unique for matrix and not present inside cells, but most of these proteins do not have well described function with respect to extracellular component of biofilm. Functional classification of enriched in matrix proteins resulted in several bioprocess groups of proteins. Top three groups were: oxidation-reduction processes, nucleoside metabolism and fatty acid synthesis. Finally, we discuss obtained data in prism of possible directions for antibiofilm therapeutic development.

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Section: Global Transcriptional Analysis Reveals Downregulation Of Ir...mentioning

confidence: 99%

“…Nucleotide biosynthesis is essential for bacterial life, with the end products involved in multiple cellular functions (Goncheva et al, 2022). In Particular, de novo pyrimidine biosynthesis ultimately produces thymine, uracil, and cytosine nucleotides, which are also modified and used for DNA and RNA replication (Goncheva et al, 2022). Our results clearly showed a significant increase in metabolites involved in the pyrimidine biosynthesis pathway (i.e., cytosine, uracil, thymidine, uridine, and UDP) in mliR cells with respect to WT cells (Figure 8C and Supplementary Figure S5).…”

Section: Global Transcriptional Analysis Reveals Downregulation Of Ir...mentioning

confidence: 99%

MliR, a novel MerR-like regulator of iron homeostasis, impacts metabolism, membrane remodeling, and cell adhesion in the marine Bacteroidetes Bizionia argentinensis

et al. 2022

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The MerR family is a group of transcriptional activators with conserved N-terminal helix-turn-helix DNA binding domains and variable C-terminal effector binding regions. In most MerR proteins the effector binding domain (EBD) contains a cysteine center suited for metal binding and mediates the response to environmental stimuli, such as oxidative stress, heavy metals or antibiotics. We here present a novel transcriptional regulator classified in the MerR superfamily that lacks an EBD domain and has neither conserved metal binding sites nor cysteine residues. This regulator from the psychrotolerant bacteria Bizionia argentinensis JUB59 is involved in iron homeostasis and was named MliR (MerR-like iron responsive Regulator). In silico analysis revealed that homologs of the MliR protein are widely distributed among different bacterial species. Deletion of the mliR gene led to decreased cell growth, increased cell adhesion and filamentation. Genome-wide transcriptomic analysis showed that genes associated with iron homeostasis were downregulated in mliR-deletion mutant. Through nuclear magnetic resonance-based metabolomics, ICP-MS, fluorescence microscopy and biochemical analysis we evaluated metabolic and phenotypic changes associated with mliR deletion. This work provides the first evidence of a MerR-family regulator involved in iron homeostasis and contributes to expanding our current knowledge on relevant metabolic pathways and cell remodeling mechanisms underlying in the adaptive response to iron availability in bacteria.

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Nucleotide biosynthesis: the base of bacterial pathogenesis

Cited by 51 publications

References 62 publications

Evolution shapes metabolic function and niche-specific antimicrobial targets in pathobionts

Evolution shapes metabolic function and niche-specific antimicrobial targets in pathobionts

Biofilm matrix proteome of clinical strain of P. aeruginosa

MliR, a novel MerR-like regulator of iron homeostasis, impacts metabolism, membrane remodeling, and cell adhesion in the marine Bacteroidetes Bizionia argentinensis

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