Genome-scale metabolic modeling in antimicrobial pharmacology

Zhu, Yan; Zhao, Jinxin; Li, Jian

doi:10.1016/j.engmic.2022.100021

Cited by 6 publications

(8 citation statements)

References 88 publications

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“…Indeed, methods have been established to develop new antibacterial drugs based on bacterial metabolism and drug-resistance mechanisms. 42 Therefore, understanding the resistance mechanisms of K. pneumoniae to antibiotics, particularly last-line antibiotics like tigecycline, helps us to establish countermeasures against antimicrobial resistance, saving patients from health costs.…”

Section: ■ Discussionmentioning

confidence: 99%

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Significant Impact of AcrB Amino Acid Polymorphism at Residue 716 on Susceptibility to Tigecycline and Other Antibiotics in Klebsiella pneumoniae

Wang,

Ma,

et al. 2024

ACS Infect. Dis.

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AcrAB-TolC is a multidrug RND-type efflux pump that is widespread in Gram-negative bacteria. As the substratebinding subunit, AcrB was shown to modulate antimicrobial resistance in Escherichia coli, but the influence of AcrB mutation on Klebsiella pneumoniae, a major clinical pathogen, has not been well-studied. The finding of an R716L mutation in AcrB in a clinical tigecycline-nonsusceptible K. pneumoniae S1 strain inspired us to probe the role of AcrB residue 716 in antimicrobial resistance. This residue was subsequently subjected to saturation mutagenesis, followed by antibiotic susceptibility tests, survival assays, and antibiotic accumulation assays, showing strong influences of AcrB mutation on antimicrobial resistance. In particular, resistance levels to azithromycin, tetracycline, tigecycline, and cefoxitin were significantly changed by AcrB mutation at residue 716. Mutations to charged residues, polar residues, and residues that disrupt secondary structures have particularly reduced the antimicrobial susceptibility of bacteria, except for azithromycin, and the impact is not due to the abolishment of the efflux function of the pump. Therefore, it is concluded that residue 716 is an important residue that significantly influences antimicrobial resistance in K. pneumoniae, adding to our understanding of antimicrobial resistance mechanisms in this key clinical pathogen.

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Section: ■ Discussionmentioning

confidence: 99%

“…pneumoniae provides clues for developing new treatment options. Indeed, methods have been established to develop new antibacterial drugs based on bacterial metabolism and drug-resistance mechanisms . Therefore, understanding the resistance mechanisms of K.…”

Section: Discussionmentioning

confidence: 99%

Significant Impact of AcrB Amino Acid Polymorphism at Residue 716 on Susceptibility to Tigecycline and Other Antibiotics in Klebsiella pneumoniae

Wang,

Ma,

et al. 2024

ACS Infect. Dis.

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“…16 GSMMs represent a valuable approach for unraveling the metabolism of pathogens and are widely employed for this purpose. 16,56 To gain a comprehensive understanding of the metabolic capabilities of H. pylori, we have updated the iIT341 model. 18 This effort was essential for improving the quality of model, and shed light on the intricate metabolic processes of H. pylori.…”

Section: Discussionmentioning

confidence: 99%

A reconstructed genome‐scale metabolic model of Helicobacter pylori for predicting putative drug targets in clarithromycin and rifampicin resistance conditions

Mofidifar,

Yadegar,

Karimi‐Jafari

2024

Helicobacter

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BackgroundHelicobacter pylori is considered a true human pathogen for which rising drug resistance constitutes a drastic concern globally. The present study aimed to reconstruct a genome‐scale metabolic model (GSMM) to decipher the metabolic capability of H. pylori strains in response to clarithromycin and rifampicin along with identification of novel drug targets.Materials and MethodsThe iIT341 model of H. pylori was updated based on genome annotation data, and biochemical knowledge from literature and databases. Context‐specific models were generated by integrating the transcriptomic data of clarithromycin and rifampicin resistance into the model. Flux balance analysis was employed for identifying essential genes in each strain, which were further prioritized upon being nonhomologs to humans, virulence factor analysis, druggability, and broad‐spectrum analysis. Additionally, metabolic differences between sensitive and resistant strains were also investigated based on flux variability analysis and pathway enrichment analysis of transcriptomic data.ResultsThe reconstructed GSMM was named as HpM485 model. Pathway enrichment and flux variability analyses demonstrated reduced activity in the ribosomal pathway in both clarithromycin‐ and rifampicin‐resistant strains. Also, a significant decrease was detected in the activity of metabolic pathways of clarithromycin‐resistant strain. Moreover, 23 and 16 essential genes were exclusively detected in clarithromycin‐ and rifampicin‐resistant strains, respectively. Based on prioritization analysis, cyclopropane fatty acid synthase and phosphoenolpyruvate synthase were identified as putative drug targets in clarithromycin‐ and rifampicin‐resistant strains, respectively.ConclusionsWe present a robust and reliable metabolic model of H. pylori. This model can predict novel drug targets to combat drug resistance and explore the metabolic capability of H. pylori in various conditions.

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“…In contrast, the theories developed for information flow (especially information theory) do not allow such modelling. 107,110,112 Similar processes may also have diverse functions among networks. For instance, while phosphorylation serves as a fuel and speeds up the reactions in metabolism, it acts as a post-translational modifier of proteins altering their activity and binding behaviour in signalling events.…”

Section: Expanding Gems Into Multi-scale and Multi-level Cellular Modelsmentioning

confidence: 99%

Genome-scale metabolic models in translational medicine: the current status and potential of machine learning in improving the effectiveness of the models

Turanli,

Gulfidan,

Aydogan

et al. 2024

Mol. Omics

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Genome-scale metabolic modeling in antimicrobial pharmacology

Cited by 6 publications

References 88 publications

Significant Impact of AcrB Amino Acid Polymorphism at Residue 716 on Susceptibility to Tigecycline and Other Antibiotics in Klebsiella pneumoniae

Significant Impact of AcrB Amino Acid Polymorphism at Residue 716 on Susceptibility to Tigecycline and Other Antibiotics in Klebsiella pneumoniae

A reconstructed genome‐scale metabolic model of Helicobacter pylori for predicting putative drug targets in clarithromycin and rifampicin resistance conditions

Genome-scale metabolic models in translational medicine: the current status and potential of machine learning in improving the effectiveness of the models

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