METABOLIC ANALYSIS OF THE MODE OF ACTION AND MODE OF RESISTANCE FOR NOVOBIOCIN IN STAPHYLOCOCCUS AUREUS

Metabolic Analysis of the Mode of Action and Mode of Resistance for Novobiocin in Staphylococcus aureus

Metabolic Analysis of the Mode of Action and Mode of Resistance for Novobiocin in Staphylococcus aureus

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Abstract: Novobiocin is an aminocoumarin antibiotic that targets DNA gyrase, a critical enzyme involved in bacterial DNA replication. In Staphylococcus aureus, resistance to novobiocin is increasingly observed, necessitating a comprehensive metabolic analysis of both its mechanism of action and resistance pathways. This study explores the metabolic disruptions induced by novobiocin and elucidates the metabolic adaptations that confer resistance in S. aureus.


Introduction: Staphylococcus aureus is a major human pathogen responsible for a variety of infections. The rise of antibiotic resistance in S. aureus, particularly to aminocoumarins like novobiocin, presents a significant clinical challenge. Understanding the metabolic consequences of novobiocin treatment and the pathways enabling resistance is essential for developing new therapeutic strategies.

Mode of Action: Novobiocin inhibits DNA gyrase by binding to the GyrB subunit, preventing ATP-dependent supercoiling of bacterial DNA. This leads to impaired DNA replication, transcription, and cell division, ultimately resulting in cell death. Metabolomic studies reveal significant disruptions in nucleotide metabolism, ATP depletion, and accumulation of DNA damage markers in susceptible S. aureus strains following novobiocin exposure.

Metabolic Impact of Novobiocin Treatment:

  1. Nucleotide Pool Disruptions: Reduced availability of dNTPs due to inhibition of DNA replication.

  2. Energy Metabolism Alterations: Decreased ATP production as a consequence of impaired ATP utilization by DNA gyrase.

  3. Oxidative Stress Response: Increased levels of reactive oxygen species (ROS) and oxidative stress markers.

  4. Lipid Metabolism Changes: Altered membrane lipid composition affecting cellular integrity.


Mode of Resistance: Novobiocin resistance in S. aureus is primarily mediated by mutations in the gyrB gene, leading to reduced binding affinity of novobiocin for DNA gyrase. Additionally, metabolic adaptations contribute to resistance:

  1. Efflux Pump Activation: Upregulation of multidrug efflux pumps such as NorA, decreasing intracellular antibiotic concentrations.

  2. Alternative Nucleotide Pathways: Enhanced salvage pathways to compensate for impaired de novo nucleotide synthesis.

  3. Energy Metabolism Shifts: Increased glycolytic activity to counteract ATP depletion.

  4. Cell Wall Modifications: Alterations in peptidoglycan structure improving resilience to DNA damage stress.

  5. Stress Response Activation: Upregulation of SOS response and DNA repair mechanisms to counteract DNA damage induced by novobiocin.


Conclusion: The metabolic analysis of novobiocin’s mode of action and resistance mechanisms in S. aureus highlights key pathways involved in antibiotic efficacy and bacterial adaptation. These findings provide potential targets for combination therapies to enhance the effectiveness of novobiocin and mitigate resistance development. Future research should focus on exploiting metabolic vulnerabilities in resistant S. aureus strains to restore antibiotic susceptibility.

Keywords: Novobiocin, Staphylococcus aureus, DNA gyrase, antibiotic resistance, metabolomics, ATP depletion, efflux pumps, oxidative stress.

https://zoonoses-journal.org/index.php/2025/01/29/gyrb-mutation-in-staphylococcus-aureus/

 

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