General Mechanisms Leading to Persister Formation and Awakening

Wilmaerts, Dorien; Windels, Etthel; Verstraeten, Natalie; Michiels, Jan

doi:10.1016/j.tig.2019.03.007

Cited by 150 publications

(165 citation statements)

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“…Thus, more cells with intrinsic antibiotic tolerance are expected to occur in biofilm population than in planktonic cultures. Given that intrinsic defense mechanisms against antibiotic-induced damages are closely linked to increased persister frequency in a bacterial population (42), we hypothesize that enrichment of drug tolerant cells in Mtb biofilms could also impact the persister frequency (Fig. 3A).…”

Section: Resultsmentioning

confidence: 99%

“…However, the correlation of a subset of these genes ( mma4 (31) , ponA2 (41) , pstA1 (40), Rv2224c (41)) with antibiotic tolerance in other studies suggests that a greater fraction of biofilm cells can survive for a longer exposure to antibiotics than planktonic cells. A logical outcome of the extended survival of the biofilm population can be hypothesized as an increase in the probability of occurrence of specialized persister cells, which emerge through mechanisms related to intrinsic defense against antibiotic-induced toxicity (42). In support of this hypothesis, we detected a lower frequency of persisters in morphologically normal biofilms of Δ pstC2A1 , providing a reasonable platform to systematically evaluate the contribution of other identified genes in this study in drug tolerance of Mtb biofilms.…”

Section: Discussionmentioning

confidence: 99%

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Adaptation of Mycobacterium tuberculosis to biofilm growth is genetically linked to drug tolerance

Richards

Cai

Zill

et al. 2019

Preprint

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21Mycobacterium tuberculosis (Mtb) spontaneously grows at the air-medium interface 22 forming pellicle biofilms, which harbor more drug tolerant persisters than planktonic 23 cultures. The underlying basis for increased persisters in Mtb biofilms is unknown. 24 Using a Tn-seq approach, we show here that multiple genes that are necessary for 25 fitness of Mtb cells within biofilms, but not in planktonic cultures, are also important for 26 their tolerance to a diverse set of stressors and antibiotics. Thus, development of Mtb 27 biofilms appears to be associated with population enrichment, in which endogenous 28 stresses presumably generated by challenging growth conditions within biofilm 29 architecture select for cells that maintain tolerance to exogenous stresses including 30 antibiotic exposure. We further observed that the intrinsic drug tolerance of constituent 31 cells of biofilms determines the frequency of persisters: morphologically 32 indistinguishable monoculture biofilms of a ΔpstC2A1 mutant hypersensitive to 33 rifampicin harbor ~20-fold fewer persisters than wild-type. These findings together allow 34 us to propose that the selection of elite cells during biofilm development significantly 35 contributes to the persister frequency. Furthermore, probing the possibility that the 36 population enrichment is an outcome of unique environment within biofilms, we 37 demonstrate biofilm-specific induction in the synthesis of isonitrile lipopeptides (INLP). 38 Mutation analysis indicates that INLP is necessary for the architecture development of 39 Mtb biofilms. In summary, the study offers an insight into persistence of Mtb biofilms 40 under antibiotic exposure, while identifying INLP as a biomarker for further investigation 41 of this phenomenon. 42 3 SIGNIFICANCE 43 The tuberculosis (TB) pathogen Mycobacterium tuberculosis (Mtb) is one of the 44 deadliest bacterial pathogens known to mankind, and TB treatment is inefficient. A 45 lengthy chemotherapy for TB is attributed to a small subpopulation of Mtb bacilli 46 exhibiting phenotypic tolerance to antibiotics. Drugs targeting these persisters are 47 55 Treatment of tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), entails a 56 multi-drug regimen administered for at least 6 months. A lengthy treatment is 57presumably necessitated by the persistence of a small subpopulation of bacilli, which 58 exhibit phenotypic tolerance to antibiotics (1, 2). Although the mechanism underlying the 59 development of Mtb persisters during infection is unclear, in vitro studies suggest that 60 these bacilli probably develop through both stochastic and induced mechanisms(3-6). 61The persistence of microbes against antibiotics has been closely linked to their 62 ability to grow as sessile, three-dimensionally organized, matrix encapsulated, 63 multicellular communities called biofilms (7-11). Biofilm-related antibiotic tolerance is 64 rendered particularly relevant by the fact that a majority of chronic microbial infections in 65 humans occur as biofi...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Adaptation of Mycobacterium tuberculosis to biofilm growth is genetically linked to drug tolerance

Richards

Cai

Zill

et al. 2019

Preprint

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“…We have shown that nutrient stress creates persister cells that are equivalent to the cells known as 15 viable but non-culturable (2). Since, nearly all tested cells form persisters (4) and almost all cells will face starvation, the persister state is probably an universal resting state (5). Unfortunately, since persister cells usually exist as a sub-population of less than 1% of cells, they have been difficult to study and little is known about how they form.…”

Section: Introductionmentioning

confidence: 99%

ppGpp Ribosome Dimerization Model for Bacterial Persister Formation and Resuscitation

Song

Wood

2019

Preprint

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Stress is ubiquitous for bacteria and converts a subpopulation of cells into a dormant state known as persistence, in which cells are tolerant to antimicrobials. These cells revive rapidly when the stress is removed and are likely the cause of many recurring infections such as those associated with tuberculosis, cystic fibrosis, and Lyme disease. However, how persister cells are formed is not understood well. Here we 5 propose the ppGpp ribosome dimerization persister (PRDP) model in which the alarmone guanosine pentaphosphate/tetraphosphate (henceforth ppGpp) generates persister cells directly by inactivating ribosomes via the ribosome modulation factor (RMF) and the hibernation promoting factor (Hpf). We demonstrate both RMF and HpF increase persistence and reduce single-cell persister resuscitation and that ppGpp has no effect on single-cell persister resuscitation. Hence, a direct connection between ppGpp and 10 persistence is shown.

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“…Persisters are found in virtually all bacteria, and persister bacteria in some pathogenic bacteria such as Mycobacterium tuberculosis , Escherichia coli , Pseudomonas aeruginosa , S. aureus , Borrelia burgdorferi , Brucella abortus etc. , are known to play important roles in causing persistent infections and post-treatment relapse, and require lengthy treatment and pose significant challenges for effective treatment and control of these infections (5–7).…”

Section: Introductionmentioning

confidence: 99%

A Novel LysR-Type Global Regulator RpvA Controls Persister Formation and Virulence inStaphylococcus aureus

Han

Liu

et al. 2019

Preprint

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9Staphylococcus aureus is the leading cause of wound and nosocomial infections. 0Persister formation and virulence factors play crucial roles during S. aureus infection. 1However, the mechanisms of persister formation and its relationship to virulence in S.3 2 aureus are poorly understood. In this study, we screened a transposon mutant library 3 3 and identified a LysR-type global transcriptional regulator NWMN_0037, which we 3 4 called RpvA, for regulator of persistence and virulence, whose mutation leads to 3 5 higher susceptibility to antibiotics ampicillin and norfloxacin and various stresses 3 6including oxidative stress, heat, and starvation in late exponential and early stationary 3 7 phase. Interestingly, the rpvA mutant was highly attenuated for virulence compared 3 8with the parent S. aureus Newman strain as shown by a much higher lethal dose, 3 9 reduced ability to survive in macrophages and to form abscess in the mouse model. 4 0 Transcriptional profiling and metabolomic analysis revealed that RpvA could repress 4 1 multiple genes including gapR, gapA, tpi, pgm, eno, glpD, and acs expression and 4 2 enhance production of numerous intermediate metabolites including 4 3 dihydroxyacetone phosphate, 2-phosphoglycerate, acetyl-CoA, glycerol 3-phosphate, 4 4 L-glutamate in the cells. The differentially expressed genes and altered production of 4 5 metabolites are distributed in global metabolism including carbohydrate metabolism, 4 6 amino acid metabolism, energy metabolism and metabolism of cofactors and vitamins. 4 7These metabolic adjustments could cause the cell to go into dormancy, thus promoting 4 8 S. aureus to convert to persisters. In addition, RpvA could upregulate the expression 4 9 of virulence genes including hla, hlgA, hlgB, hlgC, lukF, lukS, lukD, sea and coa, and 5 0

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General Mechanisms Leading to Persister Formation and Awakening

Cited by 150 publications

References 123 publications

Adaptation of Mycobacterium tuberculosis to biofilm growth is genetically linked to drug tolerance

Adaptation of Mycobacterium tuberculosis to biofilm growth is genetically linked to drug tolerance

ppGpp Ribosome Dimerization Model for Bacterial Persister Formation and Resuscitation

A Novel LysR-Type Global Regulator RpvA Controls Persister Formation and Virulence inStaphylococcus aureus

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