Abstract
Persisters are transiently tolerant variants that allow populations to avoid eradication by antibiotic treatment. Their antibiotic tolerance is non-genetic, not inheritable and results from ...a phenotypic switch from the normal, sensitive cell type to the tolerant, persister state. Here we give a comprehensive overview on bacterial persistence. We first define persistence, summarize the various aspects of persister physiology and show their heterogeneous nature. We then focus on the role of key cellular processes and mechanisms controlling the formation of a subpopulation of tolerant cells. Being a prime example of a risk-spreading strategy, we next discuss the eco-evolutionary aspects of persistence, e.g. how persistence evolves in the face of treatment with antibiotics. Finally, we illustrate the clinical importance of persisters, as persistence is worsening the worldwide antibiotic crisis by prolonging antibiotic treatment, causing therapy failure or catalyzing the development of genetically encoded antibiotic resistance. A better understanding of this phenotype is critical in our fight against pathogenic bacteria and to obtain a better outlook on future therapies.
Drug-tolerant persisters arise by various mechanisms, causing therapy failure and contributing to the ongoing antibiotic crisis.
For decades, mankind has dominated the battle against bacteria, yet the tide is slowly turning. Our antibacterial strategies are becoming less effective, allowing bacteria to get the upper hand. The ...alarming rise in antibiotic resistance is an important cause of anti-infective therapy failure. However, other factors are at play as well. It is widely recognized that bacterial populations display high levels of heterogeneity. Population heterogeneity generates phenotypes specialized in surviving antibiotic attacks. Nonetheless, the presence of antibiotic-insensitive subpopulations is not considered when initiating treatment. It is therefore time to reevaluate how we combat bacterial infections. We here focus on antibiotic persistence and heteroresistance, phenomena in which small fractions of the population are tolerant (persisters) and resistant to antibiotics, respectively. We discuss molecular mechanisms involved, their clinical importance, and possible therapeutic strategies. Moving forward, we argue that these heterogeneous phenotypes should no longer be ignored in clinical practice and that better diagnostic and therapeutic approaches are urgently needed.
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Population heterogeneity generates phenotypes specialized in surviving antibiotic attacks. Persistence and heteroresistance are examples of such heterogeneity that can lead to treatment failure. However, the presence of antibiotic-insensitive subpopulations is not considered when initiating treatment. We here discuss the molecular mechanisms involved in these phenomena, their clinical importance, and possible therapeutic strategies.
All bacterial populations harbor a small fraction of transiently antibiotic-tolerant cells called persisters. These phenotypic variants compromise successful antibiotic treatment because they are ...held responsible for the relapse of many chronic infections. In addition, studies employing experimental evolution have demonstrated that persistence contributes to the development of antibiotic resistance. Persisters are typically described as dormant cells. However, recent findings indicate a role for active mechanisms in the formation and maintenance of the persister phenotype. This review summarizes novel insights into the molecular mechanisms of persister formation and awakening, focusing on changes in cell physiology mediated by persistence effectors.
Experimental evidence is accumulating for the contribution of persister cells to the recalcitrance of chronic infections and the increased development of antibiotic resistance.Target inactivity and dormancy caused by energy loss, halted DNA replication, and blocked translation contribute to persister formation.Target inactivity and dormancy cannot fully explain the complex nature of persister cells because some persisters rely on intrinsic mechanisms to repair antibiotic damage or to lower the intracellular antibiotic concentration.Depending on the persistence effector at play, persisters can have distinct physiologies that contribute to their heterogeneity within bacterial populations.In vitro evolution experiments have shown that persistence is a highly evolvable trait.
Abstract Any bacterial population harbors a small number of phenotypic variants that survive exposure to high concentrations of antibiotic. Importantly, these so-called ‘persister cells’ compromise ...successful antibiotic therapy of bacterial infections and are thought to contribute to the development of antibiotic resistance. Intriguingly, drug-tolerant persisters have also been identified as a factor underlying failure of chemotherapy in tumor cell populations. Recent studies have begun to unravel the complex molecular mechanisms underlying persister formation and revolve around stress responses and toxin-antitoxin modules. Additionally, in vitro evolution experiments are revealing insights into the evolutionary and adaptive aspects of this phenotype. Furthermore, ever-improving experimental techniques are stimulating efforts to investigate persisters in their natural, infection-associated, in vivo environment. This review summarizes recent insights into the molecular mechanisms of persister formation, explains how persisters complicate antibiotic treatment of infections, and outlines emerging strategies to combat these tolerant cells.
Antibiotic resistance poses an alarming and ever-increasing threat to modern health care. Although the current antibiotic crisis is widely acknowledged, actions taken so far have proved insufficient ...to slow down the rampant spread of resistant pathogens. Problematically, routine screening methods and strategies to restrict therapy failure almost exclusively focus on genetic resistance, while evidence for dangers posed by other bacterial survival strategies is mounting. Antibiotic tolerance, occurring either population-wide or in a subpopulation of cells, allows bacteria to transiently overcome antibiotic treatment and is overlooked in clinical practice. In addition to prolonging treatment and causing relapsing infections, recent studies have revealed that tolerance also accelerates the emergence of resistance. These critical findings emphasize the need for strategies to combat tolerance, not only to improve treatment of recurrent infections but also to effectively address the problem of antibiotic resistance at the root.
Bacteria are well known for their extremely high adaptability in stressful environments. The clinical relevance of this property is clearly illustrated by the ever-decreasing efficacy of antibiotic ...therapies. Frequent exposures to antibiotics favor bacterial strains that have acquired mechanisms to overcome drug inhibition and lethality. Many strains, including life-threatening pathogens, exhibit increased antibiotic resistance or tolerance, which considerably complicates clinical practice. Alarmingly, recent studies show that in addition to resistance, tolerance levels of bacterial populations are extremely flexible in an evolutionary context. Here, we summarize laboratory studies providing insight in the evolution of resistance and tolerance and shed light on how the treatment conditions could affect the direction of bacterial evolution under antibiotic stress.
Living on a surface: swarming and biofilm formation Verstraeten, Natalie; Braeken, Kristien; Debkumari, Bachaspatimayum ...
Trends in microbiology (Regular ed.),
10/2008, Letnik:
16, Številka:
10
Journal Article
Recenzirano
Swarming is the fastest known bacterial mode of surface translocation and enables the rapid colonization of a nutrient-rich environment and host tissues. This complex multicellular behavior requires ...the integration of chemical and physical signals, which leads to the physiological and morphological differentiation of the bacteria into swarmer cells. Here, we provide a review of recent advances in the study of the regulatory pathways that lead to swarming behavior of different model bacteria. It has now become clear that many of these pathways also affect the formation of biofilms, surface-attached bacterial colonies. Decision-making between rapidly colonizing a surface and biofilm formation is central to bacterial survival among competitors. In the second part of this article, we review recent developments in the understanding of the transition between motile and sessile lifestyles of bacteria.
Certain infectious diseases caused by pathogenic bacteria are typically chronic in nature. Potentially deadly examples include tuberculosis, caused by Mycobacterium tuberculosis, cystic ...fibrosis-associated lung infections, primarily caused by Pseudomonas aeruginosa, and candidiasis, caused by the fungal pathogen Candida albicans. A hallmark of this type of illness is the recalcitrance to treatment with antibiotics, even in the face of laboratory tests showing the causative agents to be sensitive to drugs. Recent studies have attributed this treatment failure to the presence of a small, transiently multidrug-tolerant subpopulation of cells, so-called persister cells. Here, we review our current understanding of the role that persisters play in the treatment and outcome of chronic infections. In a second part, we offer a perspective on the development of anti-persister therapies based on genes and mechanisms that have been implicated in persistence over the last decade.
Antibiotic persistence describes the presence of phenotypic variants within an isogenic bacterial population that are transiently tolerant to antibiotic treatment. Perturbations of metabolic ...homeostasis can promote antibiotic persistence, but the precise mechanisms are not well understood. Here, we use laboratory evolution, population-wide sequencing and biochemical characterizations to identify mutations in respiratory complex I and discover how they promote persistence in Escherichia coli. We show that persistence-inducing perturbations of metabolic homeostasis are associated with cytoplasmic acidification. Such cytoplasmic acidification is further strengthened by compromised proton pumping in the complex I mutants. While RpoS regulon activation induces persistence in the wild type, the aggravated cytoplasmic acidification in the complex I mutants leads to increased persistence via global shutdown of protein synthesis. Thus, we propose that cytoplasmic acidification, amplified by a compromised complex I, can act as a signaling hub for perturbed metabolic homeostasis in antibiotic persisters.
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