Bacterial persistence promotes the evolution of antibiotic resistance by increasing survival and mutation rates

Windels, Etthel; Michiels, Joran; Fauvart, Maarten; Wenseleers, Tom; Bergh, Bram Van den; Michiels, Jan

doi:10.1038/s41396-019-0344-9

Cited by 293 publications

(280 citation statements)

References 78 publications

(118 reference statements)

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“…1E, t=0). Flow cytometry reveals ongoing cell division as a dilution of GFP, whereas the fluorescence levels are maintained 5 in the nonproliferating subpopulation ( Fig. 1E, WT at t=2.5 h).…”

Section: Deletion Of Crp and Cyaa Reduced Non-growing Cell Levels Inmentioning

confidence: 99%

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Therapeutically exploring persister metabolism in bacteria

Mohiuddin

Hoang

Saba

et al. 2019

Preprint

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8Bacterial persisters are rare phenotypic variants that are temporarily tolerant to high 9 concentrations of antibiotics. We have previously discovered that persisters are mostly 10 derived from stationary-phase cells with high redox activities that are maintained by 11 endogenous protein and RNA degradation. This intracellular degradation resulted in self- 12 inflicted damage that transiently repressed the cellular functions targeted by antibiotics. 13 Leveraging this knowledge, we developed an assay integrating a degradable fluorescent 14 protein system and a small library, containing FDA-approved drugs and antibiotics, to detect 15 chemicals that target persister metabolism. We identified several metabolic inhibitors, 16 including anti-psychotic drugs, that can reduce Escherichia coli persistence. These chemical 17 inhibitors also reduce Pseudomonas aeruginosa persistence, potentially verifying the 18 existence of similar mechanisms in a medically relevant organism. 19 20 21 22 42high redox activities that are maintained by endogenous protein and RNA degradation (12). 43 We speculated that this intracellular degradation (i.e., self-digestion or autophagy) not only 44 provides energy to bacterial cells in a non-nutritive environment, but also produces self-45 inflicted damage that renders the cells less fit for rapid resumption of growth. Inhibiting 46 stationary-phase respiratory activities chemically (treatment with potassium cyanide or 47 nitric oxide to suppress cellular respiration), environmentally (culturing under anaerobic 48 3 conditions), or even genetically (genes encoding redox enzymes such as ubiF, sucB, mdh, 49 aceE, sdhC, and acnB) reduced persister levels by preventing digestion of endogenous 50 proteins and RNA, yielding cells that were more capable of translation and replication and 51 thus susceptible to cell death when exposed to antibiotics (12, 13). This reduction in 52 persister levels was not found to be associated with the inhibition of RNA and protein 53 synthesis or elimination of reactive oxygen species (ROS) (12). These results also suggest 54 persisters harbor ETC activities associated with bacterial cytochromes, oxidoreductases and 55 PMF, which was supported by previous studies, where "aminoglycoside (AG) potentiation 56 assays" were used (14-16). Our current study further provides strong support for the notion 57 that persister metabolism is a rich source of novel antipersister strategies. Using a high-58 throughput screening approach and a small chemical library (Biolog Phenotype Arrays 59 containing FDA-approved drugs and antibiotics) in the current study, we identified a subset 60 of drugs that can reduce persistence in Gram-negative bacteria by targeting their 61 metabolism. 62 RESULTS 63Chlorpromazine pretreatment can reduce E. coli persistence 64 As effective sterilization methods for treating chronic and recurrent infections remain 65 scarce, identifying novel targets, together with medicinally relevant inhibitors, is becoming 66 an urgent priority to im...

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Section: Deletion Of Crp and Cyaa Reduced Non-growing Cell Levels Inmentioning

confidence: 99%

“…Persisters are an important health problem, because they are thought to underlie the propensity of recurrent infections to relapse [2][3][4] and serve as a reservoir from which drug-resistant mutants can emerge [5][6][7][8] . Persisters exhibit a diverse range of proliferative, metabolic, and transcriptional activities.…”

Section: Introductionmentioning

confidence: 99%

Therapeutically exploring persister metabolism in bacteria

Mohiuddin

Hoang

Saba

et al. 2019

Preprint

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“…Previous studies have demonstrated that mutations conferring antibiotic tolerance or persistence promote the evolution of antibiotic resistance 21,22 . Moreover, tolerance mutations can 1) interact synergistically with resistance mutations to increase bacterial survival during antibiotic treatment 23 and 2) promote the establishment of resistance mutations during combination drug therapy 24 .…”

Section: Pyocyanin Promotes the Evolution Of Antibiotic Resistancementioning

confidence: 99%

Bacterial defenses against a natural antibiotic promote collateral resilience to clinical antibiotics

Meirelles

Perry

Bergkessel

et al. 2020

Preprint

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As antibiotic-resistant infections become increasingly prevalent worldwide, understanding the factors that lead to antimicrobial treatment failure is essential to optimizing the use of existing drugs. Opportunistic human pathogens in particular typically exhibit high levels of intrinsic antibiotic resistance and tolerance 1 , leading to chronic infections that can be nearly impossible to eradicate 2 . We asked whether the recalcitrance of these organisms to antibiotic treatment could be driven in part by their evolutionary history as environmental microbes, which frequently produce or encounter natural antibiotics 3,4 . Using the opportunistic pathogen Pseudomonas aeruginosa as a model, we demonstrate that the self-produced natural antibiotic pyocyanin (PYO) activates bacterial defenses that confer collateral tolerance to certain synthetic antibiotics, including in a clinically-relevant growth medium. Non-PYO-producing opportunistic pathogens isolated from lung infections similarly display increased antibiotic tolerance when they are co-cultured with PYO-producing P. aeruginosa. Furthermore, we show that beyond promoting bacterial survival in the presence of antibiotics, PYO can increase the apparent rate of mutation to antibiotic resistance by up to two orders of magnitude. Our work thus suggests that bacterial production of natural antibiotics in infections could play an important role in modulating not only the immediate efficacy of clinical antibiotics, but also the rate at which antibiotic resistance arises in multispecies bacterial communities.

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“…Firstly, in studies involving long exposure of Mycobacterium tuberculosis to rifampin, Sebastian and colleagues concluded that persisters are a source of de novo resistant mutants [26]; secondly, Balaban and colleagues observed that the evolution of increased tolerance or persistence confer mutations in E. coli populations under intermittent ampicillin exposure [27]. In 2019, Windels and colleagues discovered a strong, positive correlation between persister levels and the probability of resistance evolving in natural isolates and laboratory strains of E. coli [28]. Although different types of antibiotics and different experimental conditions were used in these three studies, the results are consistent, strongly suggesting a widespread link between persistence/tolerance to antibiotics and the evolution of resistance to these drugs.…”

Section: Introductionmentioning

confidence: 99%

“…Although different types of antibiotics and different experimental conditions were used in these three studies, the results are consistent, strongly suggesting a widespread link between persistence/tolerance to antibiotics and the evolution of resistance to these drugs. Considerable efforts should hereafter be devoted to the development of strategies that can eliminate tolerant and persistent cells, which potentially favor the evolution of resistance [28].…”

Section: Introductionmentioning

confidence: 99%

Strategies to Combat Multidrug-Resistant and Persistent Infectious Diseases

et al. 2020

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Antibiotic failure is one of the most worrying health problems worldwide. We are currently facing an international crisis with several problematic facets: new antibiotics are no longer being discovered, resistance mechanisms are occurring in almost all clinical isolates of bacteria, and recurrent infections caused by persistent bacteria are hampering the successful treatment of infections. In this context, new anti-infectious strategies against multidrug-resistant (MDR) and persistent bacteria, as well as the rescue of Food and Drug Administration (FDA)-approved compounds (drug repurposing), are being explored. Among the highlighted new anti-infectious strategies, in this review, we focus on antimicrobial peptides, anti-virulence compounds, phage therapy, and new molecules. As drugs that are being repurposed, we highlight anti-inflammatory compounds, anti-psychotics, anti-helminthics, anti-cancerous drugs, and statins.

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Bacterial persistence promotes the evolution of antibiotic resistance by increasing survival and mutation rates

Cited by 293 publications

References 78 publications

Therapeutically exploring persister metabolism in bacteria

Therapeutically exploring persister metabolism in bacteria

Bacterial defenses against a natural antibiotic promote collateral resilience to clinical antibiotics

Strategies to Combat Multidrug-Resistant and Persistent Infectious Diseases

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