Persisters and beyond: mechanisms of phenotypic drug resistance and drug tolerance in bacteria.
14 Mar 2014-Critical Reviews in Biochemistry and Molecular Biology (Taylor & Francis)-Vol. 49, Iss: 2, pp 91-101
TL;DR: Mechanisms of phenotypic drug tolerance and resistance in bacteria are reviewed with the goal of providing a framework for understanding the similarities and differences in these cells.
Abstract: One of the challenges in clinical infectious diseases is the problem of chronic infections, which can require long durations of antibiotic treatment and often recur. An emerging explanation for the refractoriness of some infections to treatment is the existence of subpopulations of drug tolerant cells. While typically discussed as “persister” cells, it is becoming increasingly clear that there is significant heterogeneity in drug responses within a bacterial population and that multiple mechanisms underlie the emergence of drug tolerant and drug-resistant subpopulations. Many of these parallel mechanisms have been shown to affect drug susceptibility at the level of a whole population. Here we review mechanisms of phenotypic drug tolerance and resistance in bacteria with the goal of providing a framework for understanding the similarities and differences in these cells.
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TL;DR: This Opinion article describes recent studies of tolerance, resistance and persistence, outlining how a clear and distinct definition for each phenotype can be developed from these findings and proposes a framework for classifying the drug response of bacterial strains according to these definitions that is based on the measurement of the minimum inhibitory concentration.
Abstract: Antibiotic tolerance is associated with the failure of antibiotic treatment and the relapse of many bacterial infections. However, unlike resistance, which is commonly measured using the minimum inhibitory concentration (MIC) metric, tolerance is poorly characterized, owing to the lack of a similar quantitative indicator. This may lead to the misclassification of tolerant strains as resistant, or vice versa, and result in ineffective treatments. In this Opinion article, we describe recent studies of tolerance, resistance and persistence, outlining how a clear and distinct definition for each phenotype can be developed from these findings. We propose a framework for classifying the drug response of bacterial strains according to these definitions that is based on the measurement of the MIC together with a recently defined quantitative indicator of tolerance, the minimum duration for killing (MDK). Finally, we discuss genes that are associated with increased tolerance - the 'tolerome' - as targets for treating tolerant bacterial strains.
1,019 citations
TL;DR: This Review draws on model systems and human data to discuss multiple facets of TB biology and their relationship to the overall heterogeneity observed in the human disease.
Abstract: Infection with Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), results in a range of clinical presentations in humans. Most infections manifest as a clinically asymptomatic, contained state that is termed latent TB infection (LTBI); a smaller subset of infected individuals present with symptomatic, active TB. Within these two seemingly binary states, there is a spectrum of host outcomes that have varying symptoms, microbiologies, immune responses and pathologies. Recently, it has become apparent that there is diversity of infection even within a single individual. A good understanding of the heterogeneity that is intrinsic to TB - at both the population level and the individual level - is crucial to inform the development of intervention strategies that account for and target the unique, complex and independent nature of the local host-pathogen interactions that occur in this infection. In this Review, we draw on model systems and human data to discuss multiple facets of TB biology and their relationship to the overall heterogeneity observed in the human disease.
329 citations
TL;DR: The research status of MSSA and MRSA, the detailed mechanisms of the intrinsic antibiotic resistance and the acquired antibiotic resistance, the advanced research on anti-MRSA antibiotics and novel therapeutic strategies for MRSA treatment are reviewed.
Abstract: Infectious diseases are the second most important cause of human death worldwide; Staphylococcus aureus (S. aureus) is a very common human pathogenic microorganism that can trigger a variety of infectious diseases, such as skin and soft tissue infections, endocarditis, osteomyelitis, bacteremia, and lethal pneumonia. Moreover, according to the sensitivity to antibiotic drugs, S. aureus can be divided into methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA). In recent decades, due to the evolution of bacteria and the abuse of antibiotics, the drug resistance of S. aureus has gradually increased, the infection rate of MRSA has increased worldwide, and the clinical anti-infective treatment for MRSA has become more difficult. Accumulating evidence has demonstrated that the resistance mechanisms of S. aureus are very complex, especially for MRSA, which is resistant to many kinds of antibiotics. Therefore, understanding the drug resistance of MRSA in a timely manner and elucidating its drug resistance mechanism at the molecular level are of great significance for the treatment of S. aureus infection. A large number of researchers believe that analyzing the molecular characteristics of S. aureus can help provide a basis for designing effective prevention and treatment measures against hospital infections caused by S. aureus and further monitor the evolution of S. aureus. This paper reviews the research status of MSSA and MRSA, the detailed mechanisms of the intrinsic antibiotic resistance and the acquired antibiotic resistance, the advanced research on anti-MRSA antibiotics and novel therapeutic strategies for MRSA treatment.
298 citations
Cites background from "Persisters and beyond: mechanisms o..."
...Persisters are phenotypic variants but not mutants (Kester and Fortune, 2014)....
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...Early studies suggest that, unlike antibiotic resistance, bacterial retention is a physiological state of bacteria that temporarily resists antibiotic stress, and does not result in a change in the genotype (Kester and Fortune, 2014)....
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TL;DR: This work defines persistence, summarizes the various aspects of persister physiology and shows their heterogeneous nature, and focuses on the role of key cellular processes and mechanisms controlling the formation of a subpopulation of tolerant cells.
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.
265 citations
TL;DR: This review explores developing strategies in the context of circumventing current mechanisms of resistance into effective combination therapies designed to 1) fight the infection, 2) avoid resistance, and 3) protect the natural microbiome.
263 citations
References
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TL;DR: The features of biofilm infections are summarized, the emerging mechanisms of resistance are reviewed, and potential therapies are discussed.
4,116 citations
TL;DR: Owing to the heterogeneous nature of the biofilm, it is likely that there are multiple resistance mechanisms at work within a single community.
3,578 citations
TL;DR: Investigating the persistence of single cells of Escherichia coli with the use of microfluidic devices found phenotypic switching occurred between normally growing cells and persister cells having reduced growth rates, leading to a simple mathematical description of the persistence switch.
Abstract: A fraction of a genetically homogeneous microbial population may survive exposure to stress such as antibiotic treatment. Unlike resistant mutants, cells regrown from such persistent bacteria remain sensitive to the antibiotic. We investigated the persistence of single cells of Escherichia coli with the use of microfluidic devices. Persistence was linked to preexisting heterogeneity in bacterial populations because phenotypic switching occurred between normally growing cells and persister cells having reduced growth rates. Quantitative measurements led to a simple mathematical description of the persistence switch. Inherent heterogeneity of bacterial populations may be important in adaptation to fluctuating environments and in the persistence of bacterial infections.
2,599 citations
"Persisters and beyond: mechanisms o..." refers methods in this paper
...In a seminal work from Balaban and colleagues, a hipA mutant was used to observe high levels of persisters; their generation dynamics, b-lactam survival, and growth characteristics were assayed (Balaban et al., 2004)....
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...When compiled with their wild type E. coli data, a model evolved whereby persistence is achieved through slow or absent growth of cells (Balaban et al., 2004)....
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TL;DR: The molecular mechanisms that underlie the formation of dormant persister cells are now being unravelled and are the focus of this Review.
Abstract: Several well-recognized puzzles in microbiology have remained unsolved for decades. These include latent bacterial infections, unculturable microorganisms, persister cells and biofilm multidrug tolerance. Accumulating evidence suggests that these seemingly disparate phenomena result from the ability of bacteria to enter into a dormant (non-dividing) state. The molecular mechanisms that underlie the formation of dormant persister cells are now being unravelled and are the focus of this Review.
1,823 citations
"Persisters and beyond: mechanisms o..." refers background in this paper
...It has been proposed that persister cell formation is a major determinant of biofilm-associated antibiotic treatment failure (Lewis, 2006; Römling & Balsalobre, 2012; Spoering & Lewis, 2001)....
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...It has been proposed that persister cell formation is a major determinant of biofilm-associated antibiotic treatment failure (Lewis, 2006; Römling & Balsalobre, 2012; Spoering & Lewis, 2001)....
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TL;DR: 3 case histories-one involving Escherichia coli resistance to third-generation cephalosporins, another focusing on the emergence of vancomycin-resistant Staphylococcus aureus, and a third detailing multidrug resistance in Pseudomonas aeruginosa--are reviewed to illustrate the varied ways in which resistant bacteria develop.
1,697 citations