Mechanisms and clinical relevance of bacterial heteroresistance

Andersson, Dan I.; Nicoloff, Hervé; Hjort, Karin

doi:10.1038/s41579-019-0218-1

Cited by 339 publications

(447 citation statements)

References 133 publications

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“…Sometimes, a minority of cells in isogenic populations is able to grow during antibiotic treatments. Because these cells are normally susceptible (unlike resistant cells) and are actively growing (unlike persisters), this phenomenon has been called 'phenotypic resistance', 'adaptive resistance' or 'heteroresistance' [35][36][37]55]. Phenotypic heterogeneity allows bacterial populations to adopt a 'bet-hedging' strategy in unpredictable environments, increasing the chances that a part of the population will survive disturbances such as antibiotic treatments [34,37,40].…”

Section: (B) Phenotypic Heterogeneitymentioning

confidence: 99%

Antibiotic resilience: a necessary concept to complement antibiotic resistance?

2019

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Resilience is the capacity of systems to recover their initial state or functions after a disturbance. The concepts of resilience and resistance are complementary in ecology and both represent different aspects of the stability of ecosystems. However, antibiotic resilience is not used in clinical bacteriology whereas antibiotic resistance is a recognized major problem. To join the fields of ecology and clinical bacteriology, we first review the resilience concept from ecology, socio-ecological systems and microbiology where it is widely developed. We then review resilience-related concepts in microbiology, including bacterial tolerance and persistence, phenotypic heterogeneity and collective tolerance and resistance. We discuss how antibiotic resilience could be defined and argue that the use of this concept largely relies on its experimental measure and its clinical relevance. We review indicators in microbiology which could be used to reflect antibiotic resilience and used as valuable indicators to anticipate the capacity of bacteria to recover from antibiotic treatments.

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Section: (B) Phenotypic Heterogeneitymentioning

confidence: 99%

Antibiotic resilience: a necessary concept to complement antibiotic resistance?

2019

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“…At higher concentrations of the antibiotic, this trend is reversed. This type of concentration-dependent variable response requires different subpopulations to have variable affinity to the antibiotic and is known as "heteroresistance" (17).…”

Section: Resultsmentioning

confidence: 99%

A Mutant RNA Polymerase Activates the General Stress Response, Enabling Escherichia coli Adaptation to Late Prolonged Stationary Phase

Nandy

Chib

Seshasayee

2020

mSphere

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Escherichia coli populations undergo repeated replacement of parental genotypes with fitter variants deep in stationary phase. We isolated one such variant, which emerged after 3 weeks of maintaining an E. coli K-12 population in stationary phase. This variant displayed a small colony phenotype and slow growth and was able to outcompete its ancestor over a narrow time window in stationary phase. The variant also shows tolerance to beta-lactam antibiotics, though not previously exposed to the antibiotic. We show that an RpoC(A494V) mutation confers the slow growth and small colony phenotype on this variant. The ability of this mutation to confer a growth advantage in stationary phase depends on the availability of the stationary-phase sigma factor σS. The RpoC(A494V) mutation upregulates the σS regulon. As shown over 20 years ago, early in prolonged stationary phase, σS attenuation, but not complete loss of activity, confers a fitness advantage. Our study shows that later mutations enhance σS activity, either by mutating the gene for σS directly or via mutations such as RpoC(A494V). The balance between the activities of the housekeeping major sigma factor and σS sets up a trade-off between growth and stress tolerance, which is tuned repeatedly during prolonged stationary phase. IMPORTANCE An important general mechanism of a bacterium’s adaptation to its environment involves adjusting the balance between growing fast and tolerating stresses. One paradigm where this plays out is in prolonged stationary phase: early studies showed that attenuation, but not complete elimination, of the general stress response enables early adaptation of the bacterium E. coli to the conditions established about 10 days into stationary phase. We show here that this balance is not static and that it is tilted back in favor of the general stress response about 2 weeks later. This can be established by direct mutations in the master regulator of the general stress response or by mutations in the core RNA polymerase enzyme itself. These conditions can support the development of antibiotic tolerance although the bacterium is not exposed to the antibiotic. Further exploration of the growth-stress balance over the course of stationary phase will necessarily require a deeper understanding of the events in the extracellular milieu.

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“…In addition to possibly imposing a fitness cost on the organism, AMR gene amplifications have also been associated with the presence of antimicrobial heteroresistance (65, 67). The interplay between AMR gene amplification, heteroresistance and fitness is likely reflected in the genotype changes of patient 10 isolates given the development and subsequent reversion of porin mutations observed in those strains (Table 1).…”

Section: Discussionmentioning

confidence: 99%

Concurrence of Porin Loss and Modular Amplification of β-Lactamase Encoding Genes Drives Carbapenem Resistance in a Cohort of Recurrent Enterobacterales Bacteremia

Shropshire

Aitken

Pifer³

et al. 2019

Preprint

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30 Background 31 Carbapenem resistant Enterobacterales (CRE) remain urgent antimicrobial resistance threats. 32 Approximately half of CRE clinical isolates lack carbapenem hydrolyzing enzymes and develop 33 carbapenem resistance through alternative mechanisms. The purpose of this study was to 34 elucidate the development of carbapenem resistance mechanisms from clonal, recurrent 35 extended-spectrum b-lactamase positive Enterobacterales (ESBL-E) bacteremia isolates in a 36 vulnerable patient population. 37 Methods 38 This study investigated a historical, retrospective cohort of ESBL-E bacteremia cases in the 39 University of Texas MD Anderson Cancer Center (MDACC) from January 2015 to July 2016. 40 Phylogenetic and comparative genomic analyses were performed to identify clonal, recurrent 41 ESBL-E isolates developing carbapenem resistance. Oxford Nanopore Technology (ONT) long-42 read and Illumina short-read sequencing data were used to generate consensus assemblies and to 43 identify signatures of mobile genetic element mediated amplification and transposition of 44 antimicrobial resistance genes. Serial passaging experiments were performed on a set of clinical 45 ST131 ESBL-E isolates to recapitulate in vivo observations. qPCR and qRT-PCR were used to 46 determine respective copy number and transcript levels of b-lactamase genes. 47 Results 48 116 ESBL-E bacteremia cases were identified, 16 of which had documented recurrent infections. 49 Four serial, recurrent isolates displayed a carbapenem resistant phenotype, three without the 50 acquisition of a known carbapenemase. These three isolates had non-carbapenemase-producing 51 CRE (non-CP-CRE) mechanisms driven by IS26-and ISEcp1-mediated amplification of 52 4 respective translocatable units (TU) and transposition units (TPU) harboring both blaOXA-1 and 53 blaCTX-M variants with concomitant outer membrane porin disruption. The TU and TPU 54 structures inserted into the open reading frames of outer membrane porin genes in a subset of 55 non-CP-CRE isolates. Serial passage of an index ST131 ESBL-E isolate under selective 56 carbapenem exposure resulted in chromosomal amplification of modular, TUs harboring β-57 lactamase genes with concomitant porin inactivation, recapitulating the in vivo carbapenem 58 resistance progression. Long-read sequencing of two additional MDACC bacteremia strains 59 identified similar non-CP-CRE mechanisms observed in the serial isolates. 60 Conclusions 61 Non-CP-CRE de novo mechanisms were the primary driver of CRE development in recurrent 62 bacteremia cases within this vulnerable patient population. The incorporation of long-read ONT 63 data into AMR surveillance platforms is critical to identify high-risk CRE isolates that are 64 difficult to identify with low-resolution phenotypic and molecular characterization methods. 65 66 Keywords: 67 Non-carbapenemase-producing carbapenem resistant Enterobacterales, Oxford Nanopore 68 Technologies MinION Sequencing, Mobile Genetic Element Amplifications, Mobile Genetic 69 Element Transpositions...

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Mechanisms and clinical relevance of bacterial heteroresistance

Cited by 339 publications

References 133 publications

Antibiotic resilience: a necessary concept to complement antibiotic resistance?

Antibiotic resilience: a necessary concept to complement antibiotic resistance?

A Mutant RNA Polymerase Activates the General Stress Response, Enabling Escherichia coli Adaptation to Late Prolonged Stationary Phase

Concurrence of Porin Loss and Modular Amplification of β-Lactamase Encoding Genes Drives Carbapenem Resistance in a Cohort of Recurrent Enterobacterales Bacteremia

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