Universal antibiotic tolerance arising from antibiotic-triggered accumulation of pyocyanin in Pseudomonas aeruginosa

Zhu, Kui; Chen, Shang; Sysoeva, Tatyana A.; Li, You

doi:10.1371/journal.pbio.3000573

Cited by 64 publications

(64 citation statements)

References 29 publications

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“…S5B), which are not substrates for the efflux pumps upregulated by PYO 11 . This finding contrasts with the conclusions of two previous studies on phenazine-mediated antibiotic tolerance, which claimed that phenazines broadly increase tolerance to all classes of antibiotics except cationic peptides 9,10 . However, one study focused on colony biofilms that produced only phenazine-1-carboxylic acid and phenazine-1-carboxamide 9 , which are less toxic than PYO 8 and consequently may induce a different set of cellular responses.…”

Section: Responses To the Self-produced Natural Antibiotic Pyocyanin contrasting

confidence: 99%

“…P. aeruginosa produces several redox-active, heterocyclic compounds known as phenazines 7 . Despite possessing broad-spectrum antimicrobial activity 7 , including against P. aeruginosa itself 8 , phenazines have recently been shown to promote tolerance to clinical antibiotics under some circumstances, via mechanisms that have yet to be characterized 9,10 . Here, we sought to assess potential broader implications of the phenomenon by investigating whether phenazine-mediated tolerance to clinical antibiotics in P. aeruginosa is driven by cellular defenses that evolved to mitigate self-induced toxicity.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Responses To the Self-produced Natural Antibiotic Pyocyanin contrasting

confidence: 99%

Section: Introductionmentioning

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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“…In this regard, Pseudomonas aeruginosa provides a good illustration of evolved adaptation to such compounds: the MexGHI-OpmD pump excretes both fluoroquinolone and 5-methylphenazine-1-carboxylate, an intermediate of pyocyanin biosynthesis, which is structurally similar to PMS and activates the mexGHI-opmD operon that belongs to the SoxR regulon [ 55 – 58 ]. As a matter of fact, pyocyanin was also found to antagonize activity of many types of antibiotics including fluoroquinolone [ 5 , 59 ]. Thus, a possibility is that in E .…”

Section: Discussionmentioning

confidence: 99%

Oxidative stress antagonizes fluoroquinolone drug sensitivity via the SoxR-SUF Fe-S cluster homeostatic axis

Gerstel

Beas²,

Duverger³

et al. 2020

PLoS Genet

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The level of antibiotic resistance exhibited by bacteria can vary as a function of environmental conditions. Here, we report that phenazine-methosulfate (PMS), a redox-cycling compound (RCC) enhances resistance to fluoroquinolone (FQ) norfloxacin. Genetic analysis showed that E . coli adapts to PMS stress by making Fe-S clusters with the SUF machinery instead of the ISC one. Based upon phenotypic analysis of soxR , acrA , and micF mutants, we showed that PMS antagonizes fluoroquinolone toxicity by SoxR-mediated up-regulation of the AcrAB drug efflux pump. Subsequently, we showed that despite the fact that SoxR could receive its cluster from either ISC or SUF, only SUF is able to sustain efficient SoxR maturation under exposure to prolonged PMS period or high PMS concentrations. This study furthers the idea that Fe-S cluster homeostasis acts as a sensor of environmental conditions, and because its broad influence on cell metabolism, modifies the antibiotic resistance profile of E . coli .

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“…All our clinical strains were isolated from hospitalized patients, a host-associated environment where we may expect redox stresses such as ROS imposed by the immune system in their fight against pathogens (Puertollano et al, 2011) and by antibiotics treatment (Zhu et al, 2019). Non-producers of rhamnolipids seem less capable of dealing with oxidative stresses, and it remains unclear what selected for this loss of function in vivo.…”

Section: Discussionmentioning

confidence: 99%

Evolution and regulation of microbial secondary metabolism

Santamaria

Liao

Wang

et al. 2020

Preprint

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Many bacteria have an incredible ability to swarm cooperatively over surfaces. But swarming phenotypes can be quite different even between strains of the same species. What drives this diversity? We compared the metabolomes of 29 clinical Pseudomonas aeruginosa isolates with a range of swarming phenotypes. We identified that isolates incapable of secreting rhamnolipids—a surfactant needed for swarming—had perturbed tricarboxylic acid (TCA) cycle and amino acid pathways and grew exponentially slower in glycerol minimal medium. Analysis of the metabolome signatures and simulations using a genome-scale model led to a mechanism which joins these observations: Strains subject to higher oxidative stress levels grow slower and shut down rhamnolipids secretion, a carbon overflow mechanism possibly to direct carbon resources towards costly stress response pathways to maintain cell viability. In vitro experiments confirmed that rhamnolipid non-producers deal worse with oxidative stress, linking intracellular redox homeostasis—a individual-level trait—to swarming—a population-level behavior. This mechanism helps explain the metabolic constraints on bacteria when secreting byproducts to interact with others—competitively and cooperatively—in microbial communities.SignificanceSwarming motility has been associated with virulence of many human bacterial pathogens. The pathogen Pseudomonas aeruginosa swarms by cooperatively secreting surfactants called rhamnolipids to lubricate surfaces. To understand why some P. aeruginosa strains swarm and others do not, we combined metabolomics, computational modeling and in vitro experiments to study the different swarming behaviors of 29 isolates of Pseudomonas aeruginosa obtained from infected patients. We found that strains can only produce rhamnolipids if they can maintain redox homeostasis. We propose that single cells must have low internal redox stress levels before they can produce rhamnolipids, which work as an overflow of carbon metabolism into a cooperative secretion that brings a fitness benefit to the entire swarming population. This mechanism links single-cell physiology and a population-level cooperative behavior key to the fitness and virulence of P. aeruginosa, a major source of hospital acquired infections.SynopsisThis study combined metabolomics, computational modeling and experiments to explain the swarming diversity in Pseudomonas aeruginosa, yielding new insights on the genetic and metabolic controls of bacterial swarming behaviorRhamnolipid secretion is necessary, but insufficient, for swarmingP. aeruginosa strains unable to produce rhamnolipids in the glycerol minimal medium have perturbed metabolism, slow growth and elevated oxidative stressRhamnolipid producers cannot produce rhamnolipids in succinate as the sole carbon source which causes greater ROS (reactive oxygen species) productionThe requirement of redox homeostasis for rhamnolipid production ensures that the overflow of precious carbon for population-level benefit is prudently controlledThis study helps linking single cell physiology with collective behavior key to the fitness and virulence of a pathogenic bacterium.

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Universal antibiotic tolerance arising from antibiotic-triggered accumulation of pyocyanin in Pseudomonas aeruginosa

Cited by 64 publications

References 29 publications

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

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

Oxidative stress antagonizes fluoroquinolone drug sensitivity via the SoxR-SUF Fe-S cluster homeostatic axis

Evolution and regulation of microbial secondary metabolism

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