(p)ppGpp and Its Role in Bacterial Persistence: New Challenges

Pacios, Olga; Blasco, Lucía; Bleriot, Inés; Fernández-García, Laura; Ambroa, Antón; López, María; Bou, Germán; Cantón, Rafael; García‐Contreras, Rodolfo; Wood, Thomas K.; Tomás, María

doi:10.1128/aac.01283-20

Cited by 90 publications

(89 citation statements)

References 106 publications

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“…The alarmone molecule guanosine pentaphosphate/tetraphosphate, (p)ppGpp, has been shown to control the expression of TA systems and play important roles in persister formation as well as the bacterial response to environmental stresses, such as oxidative stress, starvation, etc. [ 59 , 60 ]. Meanwhile, it has been demonstrated that (p)ppGpp controls global gene expression and contributes to bacterial virulence in various infection models [ 61 , 62 , 63 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of a Toxin–Antitoxin System That Contributes to Persister Formation by Reducing NAD in Pseudomonas aeruginosa

Zhou

et al. 2021

Microorganisms

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Bacterial persisters are slow-growing or dormant cells that are highly tolerant to bactericidal antibiotics and contribute to recalcitrant and chronic infections. Toxin/antitoxin (TA) systems play important roles in controlling persister formation. Here, we examined the roles of seven predicted type II TA systems in the persister formation of a Pseudomonas aeruginosa wild-type strain PA14. Overexpression of a toxin gene PA14_51010 or deletion of the cognate antitoxin gene PA14_51020 increased the bacterial tolerance to antibiotics. Co-overexpression of PA14_51010 and PA14_51020 or simultaneous deletion of the two genes resulted in a wild-type level survival rate following antibiotic treatment. The two genes were located in the same operon that was repressed by PA14_51020. We further demonstrated the interaction between PA14_51010 and PA14_51020. Sequence analysis revealed that PA14_51010 contained a conserved RES domain. Overexpression of PA14_51010 reduced the intracellular level of nicotinamide adenine dinucleotide (NAD+). Mutation of the RES domain abolished the abilities of PA14_51010 in reducing NAD+ level and promoting persister formation. In addition, overproduction of NAD+ by mutation in an nrtR gene counteracted the effect of PA14_51010 overexpression in promoting persister formation. In combination, our results reveal a novel TA system that contributes to persister formation through reducing the intracellular NAD+ level in P. aeruginosa.

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Section: Discussionmentioning

confidence: 99%

Identification of a Toxin–Antitoxin System That Contributes to Persister Formation by Reducing NAD in Pseudomonas aeruginosa

Zhou

et al. 2021

Microorganisms

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“…Studies are ongoing to find drugs that would inhibit Rel proteins (11, 13), as such drugs are expected to increase susceptibility to other clinically available antibiotics. Our results indicate that Rel inhibitors, should they become available, might actually increase tolerance when administered in combination with amikacin to treat Mab infections, and may have no effect with clarithromycin and cefoxitin.…”

Section: Resultsmentioning

confidence: 99%

“…1). In many species, the stringent response upregulates stress response genes such as heat shock proteins, hibernation factors, and stress-specific transcription factors (3, 41, 42) and promotes survival in stress (13) (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

InMycobacterium abscessus, the stringent factor Rel regulates metabolism, but is not the only (p)ppGpp synthase

Hunt-Serracin

Boll

Boutte

2020

Preprint

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The stringent response is a broadly conserved stress response system that exhibits functional variability across bacterial clades. Here, we characterize the role of the stringent factor Rel in the non-tuberculous mycobacterial pathogen, Mycobacterium abscessus (Mab). We find that Rel in Mab is involved in restricting transcription of anabolism and growth genes in stress, as has been observed in many other species. However, the stringent response in Mab does not provide a survival advantage in several stress conditions or in antibiotic treatment. According to our transcriptional profiling, Rel in Mab does not activate transcription of stress response or antibiotic resistance genes. Instead, Rel actually represses transcription of many antibiotic resistance genes in stress. This study implies that combinatorial therapies with stringent factor inhibitors would not potentiate antibiotic treatment against Mab infections.

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“…Moreover, reconstruction of this mutant strain demonstrated that deletion of the 10 TA systems did not affect susceptibility to ofloxacin or ampicillin [106]. These contradictory findings have given rise to considerable debate [78,[107][108][109], and the relevance of TA systems to bacterial persistence remains unclear.…”

Section: Role Of Type II Ta Modules In Biofilm Formation and Bacteriamentioning

confidence: 98%

Targeting Type II Toxin–Antitoxin Systems as Antibacterial Strategies

Równicki

Lasek

Trylska

et al. 2020

Toxins

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The identification of novel targets for antimicrobial agents is crucial for combating infectious diseases caused by evolving bacterial pathogens. Components of bacterial toxin–antitoxin (TA) systems have been recognized as promising therapeutic targets. These widespread genetic modules are usually composed of two genes that encode a toxic protein targeting an essential cellular process and an antitoxin that counteracts the activity of the toxin. Uncontrolled toxin expression may elicit a bactericidal effect, so they may be considered “intracellular molecular bombs” that can lead to elimination of their host cells. Based on the molecular nature of antitoxins and their mode of interaction with toxins, TA systems have been classified into six groups. The most prevalent are type II TA systems. Due to their ubiquity among clinical isolates of pathogenic bacteria and the essential processes targeted, they are promising candidates for the development of novel antimicrobial strategies. In this review, we describe the distribution of type II TA systems in clinically relevant human pathogens, examine how these systems could be developed as the targets for novel antibacterials, and discuss possible undesirable effects of such therapeutic intervention, such as the induction of persister cells, biofilm formation and toxicity to eukaryotic cells.

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(p)ppGpp and Its Role in Bacterial Persistence: New Challenges

Cited by 90 publications

References 106 publications

Identification of a Toxin–Antitoxin System That Contributes to Persister Formation by Reducing NAD in Pseudomonas aeruginosa

Identification of a Toxin–Antitoxin System That Contributes to Persister Formation by Reducing NAD in Pseudomonas aeruginosa

InMycobacterium abscessus, the stringent factor Rel regulates metabolism, but is not the only (p)ppGpp synthase

Targeting Type II Toxin–Antitoxin Systems as Antibacterial Strategies

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