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Etienne Maisonneuve

Bio: Etienne Maisonneuve is an academic researcher from Aix-Marseille University. The author has contributed to research in topics: Stringent response & Protein aggregation. The author has an hindex of 16, co-authored 21 publications receiving 3027 citations. Previous affiliations of Etienne Maisonneuve include Newcastle University & Free University of Berlin.

Papers
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Journal ArticleDOI
16 Dec 2016-Science
TL;DR: The results confirm the long-standing notion that persistence is intimately connected to slow growth or dormancy in the sense that a certain level of physiological quiescence is attained and offer insights into the molecular basis and control of bacterial persistence.
Abstract: BACKGROUND The escalating crisis of multidrug resistance is raising fears of untreatable infections caused by bacterial “superbugs.” However, many patients already suffer from infections that are effectively untreatable due to innate bacterial mechanisms for persistence. This phenomenon is caused by the formation of specialized persister cells that evade antibiotic killing and other stresses by entering a physiologically dormant state, irrespective of whether they possess genes enabling antibiotic resistance. The recalcitrance of persister cells is a major cause of prolonged and recurrent courses of infection that can eventually lead to complete antibiotic treatment failure. Regularly growing bacteria differentiate into persister cells stochastically at a basal rate, but this phenotypic conversion can also be induced by environmental cues indicative of imminent threats for the bacteria. Size and composition of the persister subpopulation in bacterial communities are largely controlled by stress signaling pathways, such as the general stress response or the SOS response, in conjunction with the second messenger (p)ppGpp that is almost always involved in persister formation. Consequently, persister formation is stimulated under conditions that favor the activation of these signaling pathways. Such conditions include bacterial biofilms and hostile host environments, as well as response to damage caused by sublethal concentrations of antibiotics. ADVANCES The limited comprehensive understanding of persister formation and survival is a critical issue in controlling persistent infections. However, recent work in the field has uncovered the molecular architecture of several cellular pathways underlying bacterial persistence, as well as the functional interactions that generate heterogeneous populations of persister cells. These results confirm the long-standing notion that persistence is intimately connected to slow growth or dormancy in the sense that a certain level of physiological quiescence is attained. Most prominently, the central role of toxin-antitoxin (TA) modules has been explained in considerable detail. In the model organism Escherichia coli K-12, two major pathways of persister formation via TA modules are both controlled by (p)ppGpp and involve toxin HokB and a panel of mRNA endonuclease toxins, respectively. Whereas activation of the membrane-associated toxin HokB depends on the enigmatic (GTPase) guanosine triphosphatase Obg and causes persister formation by abolishing the proton-motive force, mRNA endonuclease toxins are activated through antitoxin degradation by protease Lon and globally inhibit translation. In addition to these two pathways, toxin TisB is activated in response to DNA damage by the SOS response and promotes persister formation in a manner similar to HokB. Beyond TA modules, many additional factors (such as cellular energy metabolism or drug efflux) have been found to contribute to persister formation and survival, but their position in particular molecular pathways is often unclear. Altogether, this diversity of mechanisms drives the formation of a highly heterogeneous ensemble of persister cells that displays multistress and multidrug tolerance as the root of the recalcitrance of persistent infections. OUTLOOK Though recent advances in the field have greatly expanded our understanding of the molecular mechanisms underlying persister formation, important facets have remained elusive and should be addressed in future studies. One example is the upstream signaling input into the pathways mediating bacterial persister formation (e.g., the nature of the pacemaker driving stochastic persister formation). Similarly, it is often not well understood how—beyond the general idea of dormancy—persister cells can survive the action of lethal antibiotics. Finally, one curious aspect of the persister field is recurrent inconsistency between the results obtained by different groups. We speculate that these variations may be linked to subtle differences in experimental procedures inducing separate yet partially redundant pathways of persister formation. It is evident that the elucidation of this phenomenon may not only consolidate progress in the field but also offer the chance to gain insights into the molecular basis and control of bacterial persistence.

611 citations

Journal ArticleDOI
24 Apr 2014-Cell
TL;DR: Recent progress in the field is summarized, revealing the ubiquitous bacterial stress alarmone ppGpp as an emerging central regulator of multidrug tolerance and persistence, both in stochastically and environmentally induced persistence.

543 citations

Journal ArticleDOI
TL;DR: It is shown that the ubiquitous Lon (Long Form Filament) protease and mRNA endonucleases (mRNases) encoded by toxin-antitoxin (TA) loci are required for persistence in Escherichia coli.
Abstract: Bacteria form persisters, individual cells that are highly tolerant to different types of antibiotics. Persister cells are genetically identical to nontolerant kin but have entered a dormant state in which they are recalcitrant to the killing activity of the antibiotics. The molecular mechanisms underlying bacterial persistence are unknown. Here, we show that the ubiquitous Lon (Long Form Filament) protease and mRNA endonucleases (mRNases) encoded by toxin-antitoxin (TA) loci are required for persistence in Escherichia coli. Successive deletion of the 10 mRNase-encoding TA loci of E. coli progressively reduced the level of persisters, showing that persistence is a phenotype common to TA loci. In all cases tested, the antitoxins, which control the activities of the mRNases, are Lon substrates. Consistently, cells lacking lon generated a highly reduced level of persisters. Moreover, Lon overproduction dramatically increased the levels of persisters in wild-type cells but not in cells lacking the 10 mRNases. These results support a simple model according to which mRNases encoded by TA loci are activated in a small fraction of growing cells by Lon-mediated degradation of the antitoxins. Activation of the mRNases, in turn, inhibits global cellular translation, and thereby induces dormancy and persistence. Many pathogenic bacteria known to enter dormant states have a plethora of TA genes. Therefore, in the future, the discoveries described here may lead to a mechanistic understanding of the persistence phenomenon in pathogenic bacteria.

481 citations

Journal ArticleDOI
29 Aug 2013-Cell
TL;DR: It is shown that an exponentially growing population of wild-type Escherichia coli cells produces rare cells that stochastically switch into slow growth, that the slow-growing cells are multidrug tolerant, and that they are able to resuscitate.

447 citations

Journal ArticleDOI
TL;DR: It is now important to challenge this model and to test whether the persistence of pathogenic bacteria also depends on TA loci, as it is shown that persistence of the model organism Escherichia coli depends on toxin-antitoxin loci.
Abstract: Bacterial persistence is caused by the presence of rare, slowly growing bacteria among populations of rapidly growing cells. The slowly growing bacteria are tolerant of antibiotics and other environmental insults, whereas their isogenic, rapidly growing siblings are sensitive. Recent research has shown that persistence of the model organism Escherichia coli depends on toxin-antitoxin (TA) loci. Deletion of type II TA loci reduces the level of persistence significantly. Lon protease but no other known ATP-dependent proteases is required for persistence. Polyphosphate and (p)ppGpp also are required for persistence. These observations led to the proposal of a simple and testable model that explains the persistence of E. coli. It is now important to challenge this model and to test whether the persistence of pathogenic bacteria also depends on TA loci.

352 citations


Cited by
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Journal ArticleDOI
TL;DR: The fundamental role of the biofilm matrix is considered, describing how the characteristic features of biofilms — such as social cooperation, resource capture and enhanced survival of exposure to antimicrobials — all rely on the structural and functional properties of the matrix.
Abstract: Bacterial biofilms are formed by communities that are embedded in a self-produced matrix of extracellular polymeric substances (EPS). Importantly, bacteria in biofilms exhibit a set of 'emergent properties' that differ substantially from free-living bacterial cells. In this Review, we consider the fundamental role of the biofilm matrix in establishing the emergent properties of biofilms, describing how the characteristic features of biofilms - such as social cooperation, resource capture and enhanced survival of exposure to antimicrobials - all rely on the structural and functional properties of the matrix. Finally, we highlight the value of an ecological perspective in the study of the emergent properties of biofilms, which enables an appreciation of the ecological success of biofilms as habitat formers and, more generally, as a bacterial lifestyle.

3,277 citations

Journal ArticleDOI
TL;DR: A historic perspective on the development of the field is provided, common trends are emphasized, and new directions in c-di-GMP research are highlighted that will give a deeper understanding of this truly universal bacterial second messenger.
Abstract: SUMMARY Twenty-five years have passed since the discovery of cyclic dimeric (3′→5′) GMP (cyclic di-GMP or c-di-GMP). From the relative obscurity of an allosteric activator of a bacterial cellulose synthase, c-di-GMP has emerged as one of the most common and important bacterial second messengers. Cyclic di-GMP has been shown to regulate biofilm formation, motility, virulence, the cell cycle, differentiation, and other processes. Most c-di-GMP-dependent signaling pathways control the ability of bacteria to interact with abiotic surfaces or with other bacterial and eukaryotic cells. Cyclic di-GMP plays key roles in lifestyle changes of many bacteria, including transition from the motile to the sessile state, which aids in the establishment of multicellular biofilm communities, and from the virulent state in acute infections to the less virulent but more resilient state characteristic of chronic infectious diseases. From a practical standpoint, modulating c-di-GMP signaling pathways in bacteria could represent a new way of controlling formation and dispersal of biofilms in medical and industrial settings. Cyclic di-GMP participates in interkingdom signaling. It is recognized by mammalian immune systems as a uniquely bacterial molecule and therefore is considered a promising vaccine adjuvant. The purpose of this review is not to overview the whole body of data in the burgeoning field of c-di-GMP-dependent signaling. Instead, we provide a historic perspective on the development of the field, emphasize common trends, and illustrate them with the best available examples. We also identify unresolved questions and highlight new directions in c-di-GMP research that will give us a deeper understanding of this truly universal bacterial second messenger.

1,391 citations

Journal ArticleDOI
TL;DR: Strategies to re-establish viable platforms for antibiotic discovery include investigating untapped natural product sources such as uncultured bacteria, establishing rules of compound penetration to enable the development of synthetic antibiotics, developing species-specific antibiotics and identifying prodrugs that have the potential to eradicate dormant persisters, which are often responsible for hard-to-treat infections.
Abstract: The spread of resistant bacteria, leading to untreatable infections, is a major public health threat but the pace of antibiotic discovery to combat these pathogens has slowed down. Most antibiotics were originally isolated by screening soil-derived actinomycetes during the golden era of antibiotic discovery in the 1940s to 1960s. However, diminishing returns from this discovery platform led to its collapse, and efforts to create a new platform based on target-focused screening of large libraries of synthetic compounds failed, in part owing to the lack of penetration of such compounds through the bacterial envelope. This article considers strategies to re-establish viable platforms for antibiotic discovery. These include investigating untapped natural product sources such as uncultured bacteria, establishing rules of compound penetration to enable the development of synthetic antibiotics, developing species-specific antibiotics and identifying prodrugs that have the potential to eradicate dormant persisters, which are often responsible for hard-to-treat infections.

1,221 citations

Journal ArticleDOI
24 Apr 2014-Cell
TL;DR: This work presents a genome-wide approach, based on ribosome profiling, for measuring absolute protein synthesis rates, and reveals how general principles, important both for understanding natural systems and for synthesizing new ones, emerge from quantitative analyses of protein synthesis.

1,115 citations

Journal ArticleDOI
TL;DR: This Review summarized the current knowledge of oxidative stress in Escherichia coli, the model organism for which the understanding of damage and defence is most well developed, and proposed strategies to protect themselves with scavenging enzymes and repair systems.
Abstract: Oxic environments are hazardous. Molecular oxygen adventitiously abstracts electrons from many redox enzymes, continuously forming intracellular superoxide and hydrogen peroxide. These species can destroy the activities of metalloenzymes and the integrity of DNA, forcing organisms to protect themselves with scavenging enzymes and repair systems. Nevertheless, elevated levels of oxidants quickly poison bacteria, and both microbial competitors and hostile eukaryotic hosts exploit this vulnerability by assaulting these bacteria with peroxides or superoxide-forming antibiotics. In response, bacteria activate elegant adaptive strategies. In this Review, I summarize our current knowledge of oxidative stress in Escherichia coli, the model organism for which our understanding of damage and defence is most well developed.

1,107 citations