Intracellular persister: A stealth agent recalcitrant to antibiotics

Personnic, Nicolas; Doublet, Patricia; Jarraud, Sophie

doi:10.3389/fcimb.2023.1141868

Cited by 8 publications

(3 citation statements)

References 82 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The host environment is a critical determinant of antibiotic efficacy [ 2 , 38 , 39 ]. However, little is known about which host factors synergize or antagonize the action of antimicrobials during infection.…”

Section: Discussionmentioning

confidence: 99%

Intoxication of antibiotic persisters by host RNS inactivates their efflux machinery during infection

Ronneau,

Michaux,

Giorgio

et al. 2024

PLoS Pathog

View full text Add to dashboard Cite

The host environment is of critical importance for antibiotic efficacy. By impacting bacterial machineries, stresses encountered by pathogens during infection promote the formation of phenotypic variants that are transiently insensitive to the action of antibiotics. It is assumed that these recalcitrant bacteria—termed persisters—contribute to antibiotic treatment failure and relapsing infections. Recently, we demonstrated that host reactive nitrogen species (RNS) transiently protect persisters against the action of β-lactam antibiotics by delaying their regrowth within host cells. Here, we discovered that RNS intoxication of persisters also collaterally sensitizing them to fluoroquinolones during infection, explaining the higher efficiency of fluoroquinolones against intramacrophage Salmonella. By reducing bacterial respiration and the proton-motive force, RNS inactivate the AcrAB efflux machinery of persisters, facilitating the accumulation of fluoroquinolones intracellularly. Our work shows that target inactivity is not the sole reason for Salmonella persisters to withstand antibiotics during infection, with active efflux being a major contributor to survival. Thus, understanding how the host environment impacts persister physiology is critical to optimize antibiotics efficacy during infection.

show abstract

Section: Discussionmentioning

confidence: 99%

Intoxication of antibiotic persisters by host RNS inactivates their efflux machinery during infection

Ronneau,

Michaux,

Giorgio

et al. 2024

PLoS Pathog

View full text Add to dashboard Cite

show abstract

“…They are a major contributor to treatment failure and recalcitrance of chronic infections as those in CF patients. Besides stochastic generation in bacterial populations [ 32 ], environmental stress is believed to trigger persister formation as well [ 31 , 33 ]. While persister cells have been identified in all major pathogens, only a few studies have investigated the switch to the persister phenotype within eukaryotic cells [ 34–36 ].…”

Section: Introductionmentioning

confidence: 99%

Protozoan predation enhances stress resistance and antibiotic tolerance in Burkholderia cenocepacia by triggering the SOS response

Morón,

Tarhouchi,

Belinchón

et al. 2024

The ISME Journal

View full text Add to dashboard Cite

Bacterivorous protists are thought to serve as training grounds for bacterial pathogens by subjecting them to the same hostile conditions that they will encounter in the human host. Bacteria that survive intracellular digestion exhibit enhanced virulence and stress resistance after successful passage through protozoa but the underlying mechanisms are unknown. Here we show that the opportunistic pathogen Burkholderia cenocepacia survives phagocytosis by ciliates found in domestic and hospital sink drains, and viable bacteria are expelled packaged in respirable membrane vesicles with enhanced resistance to oxidative stress, desiccation and antibiotics, thereby contributing to pathogen dissemination in the environment. Reactive oxygen species generated within the protozoan phagosome promote the formation of persisters tolerant to ciprofloxacin by activating the bacterial SOS response. In addition, we show that genes encoding antioxidant enzymes are upregulated during passage through ciliates increasing bacterial resistance to oxidative radicals. We prove that suppression of the SOS response impairs bacterial intracellular survival and persister formation within protists. This study highlights the significance of protozoan food vacuoles as niches that foster bacterial adaptation in natural and built environments and suggests that persister switch within phagosomes may be a widespread phenomenon in bacteria surviving intracellular digestion.

show abstract

“…One of the mechanisms bacteria have adopted is the formation of persister cells. Persisters are nongrowing or metabolically less active cells that can survive high antibiotic concentrations without being resistant (Lewis, 2010;Personnic et al, 2023). Upon favorable conditions, persisters become metabolically active, regain their virulence potential, and resuscitate the whole population that remains fully susceptible to antibiotics (Eisenreich et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Teicoplanin associated gene tcaA inactivation increases persister cell formation in Staphylococcus aureus

Habib,

Gul,

Ahmad

et al. 2023

Front. Microbiol.

View full text Add to dashboard Cite

Staphylococcus aureus is part of normal human flora and is widely associated with hospital-acquired bacteremia. S. aureus has shown a diverse array of resistance to environmental stresses and antibiotics. Methicillin-resistant S. aureus (MRSA) is on the high priority list of new antibiotics discovery and glycopeptides are considered the last drug of choice against MRSA. S. aureus has developed resistance against glycopeptides and the emergence of vancomycin-intermediate-resistant, vancomycin-resistant, and teicoplanin-resistant strains is globally reported. Teicoplanin-associated genes tcaR-tcaA-tcaB (tcaRAB) is known as the S. aureus glycopeptide resistance operon that is associated with glycopeptide resistance. Here, for the first time, the role of tcaRAB in S. aureus persister cells formation, and ΔtcaA dependent persisters’ ability to resuscitate the bacterial population was explored. We recovered a clinical strain of MRSA from a COVID-19 patient which showed a high level of resistance to teicoplanin, vancomycin, and methicillin. Whole genome RNA sequencing revealed that the tcaRAB operon expression was altered followed by high expression of glyS and sgtB. The RNA-seq data revealed a significant decrease in tcaA (p = 0.008) and tcaB (p = 0.04) expression while tcaR was not significantly altered. We knocked down tcaA, tcaB, and tcaR using CRISPR-dCas9 and the results showed that when tcaA was suppressed by dCas9, a significant increase was witnessed in persister cells while tcaB suppression did not induce persistence. The results were further evaluated by creating a tcaA mutant that showed ΔtcaA formed a significant increase in persisters in comparison to the wild type. Based on our findings, we concluded that tcaA is the gene that increases persister cells and glycopeptide resistance and could be a potential therapeutic target in S. aureus.

show abstract

Intracellular persister: A stealth agent recalcitrant to antibiotics

Cited by 8 publications

References 82 publications

Intoxication of antibiotic persisters by host RNS inactivates their efflux machinery during infection

Intoxication of antibiotic persisters by host RNS inactivates their efflux machinery during infection

Protozoan predation enhances stress resistance and antibiotic tolerance in Burkholderia cenocepacia by triggering the SOS response

Teicoplanin associated gene tcaA inactivation increases persister cell formation in Staphylococcus aureus

Contact Info

Product

Resources

About