Host Cell Oxidative Stress Promotes Intracellular Fluoroquinolone Persisters of Streptococcus pneumoniae

Hernandez-Morfa, Mirelys; Reinoso-Vizcaíno, Nicolás M.; Olivero, Nadia B.; Zappia, Victoria E; Cortes, Paulo R.; Jaime, Andrea; Echenique, José I. Rojas

doi:10.1128/spectrum.04364-22

Cited by 9 publications

(7 citation statements)

References 70 publications

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“…This phenomenon was observed not only in bacterial cultures but also during the temporary intracellular existence of pneumococci within pneumocytes, macrophages, or neutrophils. To our knowledge, this is the first reported mechanism of antibiotic persistence in S. pneumoniae (Hernandez-Morfa et al, 2022). Exposure to oxidative stress was found to upregulate the expression of two enzymes, SodA and TpxD, which provide protection against ROS induced by FQs and enhance the intracellular survival of S. pneumoniae (Figure 4).…”

Section: Antibiotic Persistencementioning

confidence: 89%

The oxidative stress response of Streptococcus pneumoniae: its contribution to both extracellular and intracellular survival

Hernandez-Morfa,

Olivero,

Zappia

et al. 2023

Front. Microbiol.

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Streptococcus pneumoniae is a gram-positive, aerotolerant bacterium that naturally colonizes the human nasopharynx, but also causes invasive infections and is a major cause of morbidity and mortality worldwide. This pathogen produces high levels of H2O2 to eliminate other microorganisms that belong to the microbiota of the respiratory tract. However, it also induces an oxidative stress response to survive under this stressful condition. Furthermore, this self-defense mechanism is advantageous in tolerating oxidative stress imposed by the host’s immune response. This review provides a comprehensive overview of the strategies employed by the pneumococcus to survive oxidative stress. These strategies encompass the utilization of H2O2 scavengers and thioredoxins, the adaptive response to antimicrobial host oxidants, the regulation of manganese and iron homeostasis, and the intricate regulatory networks that control the stress response. Here, we have also summarized less explored aspects such as the involvement of reparation systems and polyamine metabolism. A particular emphasis is put on the role of the oxidative stress response during the transient intracellular life of Streptococcus pneumoniae, including coinfection with influenza A and the induction of antibiotic persistence in host cells.

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Section: Antibiotic Persistencementioning

confidence: 89%

The oxidative stress response of Streptococcus pneumoniae: its contribution to both extracellular and intracellular survival

Hernandez-Morfa,

Olivero,

Zappia

et al. 2023

Front. Microbiol.

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“…Oxidation of dCTP underlies antibiotic lethality mediated by reactive oxygen species in mycobacteria via induction of double-stranded breaks in genomic DNA ( 62 ), similar to our observations of decreased DNA fragmentation in the ∆ spxB ∆ lctO double mutant following fluoroquinolone treatment. In contrast, increased reactive oxygen species levels in host cells infected by pneumococci can induce intracellular bacterial tolerant cells recalcitrant to fluoroquinolone-mediated killing ( 67 ). Induction of oxidative stress responses can result in a dramatic increase in the capacity of tolerant cells to survive treatment with fluoroquinolones via increased expression of multidrug-resistance pumps ( 68 ).…”

Section: Discussionmentioning

confidence: 99%

Streptococcus pneumoniae favors tolerance via metabolic adaptation over resistance to circumvent fluoroquinolones

Dao,

Echlin,

McKnight

et al. 2024

mBio

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Streptococcus pneumoniae is a major human pathogen of global health concern and the rapid emergence of antibiotic resistance poses a serious public health problem worldwide. Fluoroquinolone resistance in S. pneumoniae is an intriguing case because the prevalence of fluoroquinolone resistance does not correlate with increasing usage and has remained rare. Our data indicate that deleterious fitness costs in the mammalian host constrain the emergence of fluoroquinolone resistance both by de novo mutation and recombination. S. pneumoniae was able to circumvent such deleterious fitness costs via the development of antibiotic tolerance through metabolic adaptation that reduced the production of reactive oxygen species, resulting in a fitness benefit during infection of mice treated with fluoroquinolones. These data suggest that the emergence of fluoroquinolone resistance is tightly constrained in S. pneumoniae by fitness tradeoffs and that mutational pathways involving metabolic networks to enable tolerance phenotypes are an important contributor to the evasion of antibiotic-mediated killing. IMPORTANCE The increasing prevalence of antibiotic resistant bacteria is a major global health concern. While many species have the potential to develop antibiotic resistance, understanding the barriers to resistance emergence in the clinic remains poorly understood. A prime example of this is fluroquinolone resistance in Streptococcus pneumoniae , whereby, despite continued utilization, resistance to this class of antibiotic remains rare. In this study, we found that the predominant pathways for developing resistance to this antibiotic class severely compromised the infectious capacity of the pneumococcus, providing a key impediment for the emergence of resistance. Using in vivo models of experimental evolution, we found that S. pneumoniae responds to repeated fluoroquinolone exposure by modulating key metabolic pathways involved in the generation of redox molecules, which leads to antibiotic treatment failure in the absence of appreciable shifts in resistance levels. These data underscore the complex pathways available to pathogens to evade antibiotic mediating killing via antibiotic tolerance.

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“…1 In recent years, the abuse of antibiotics has led to the rapid emergence of multi-drug resistant bacteria, which has been a serious problem worldwide. 2,3 Staphylococcus aureus (S. aureus) is the most typical example, and it is also the most common of hospital community and acquired infections. Pneumonia, endocarditis, inflammatory osteomyelitis and sepsis have all been implicated.…”

Section: Introductionmentioning

confidence: 99%

Ruthenium terpyridine complexes based on dppz ligands as photodynamic antimicrobial agents against Staphylococcus aureus

Wang,

Shi,

Zhu

et al. 2024

New J. Chem.

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Host Cell Oxidative Stress Promotes Intracellular Fluoroquinolone Persisters of Streptococcus pneumoniae

Cited by 9 publications

References 70 publications

The oxidative stress response of Streptococcus pneumoniae: its contribution to both extracellular and intracellular survival

The oxidative stress response of Streptococcus pneumoniae: its contribution to both extracellular and intracellular survival

Streptococcus pneumoniae favors tolerance via metabolic adaptation over resistance to circumvent fluoroquinolones

Ruthenium terpyridine complexes based on dppz ligands as photodynamic antimicrobial agents against Staphylococcus aureus

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