Mutation discovery in bacterial genomes: metronidazole resistance in Helicobacter pylori

Albert, Thomas; Dailidiene, Daiva; Dailide, Giedrius; Norton, Jason E.; Kalia, Awdhesh; Richmond, Todd; Molla, Michael; Singh, Jaz; Green, Roland D.; Berg, Douglas E.

doi:10.1038/nmeth805

Cited by 185 publications

(158 citation statements)

References 15 publications

Supporting

Mentioning

155

Contrasting

Order By: Relevance

“…A comparison with the literature lead us to believe that this result is probably not peculiar to our specific conditions, but rather it could be fairly general. While our system, in fact, exhibited substantial flexibility in evolutionary trajectories, this flexibility is similar to what is typically observed in many bacterial evolution experiments [51]: hard adaptive constraints are rarely observed at the nucleotide level [52], and even in the examples that reported the highest degree of molecular convergence, adaptation involved more than one loci and featured a considerable amount of intralocus diversity [53][54][55]. Therefore, given that mutational target sizes seem not strictly limited, we expect spectrum effects on evolvability to be modest at best in most cases.…”

Section: Discussionsupporting

confidence: 81%

Bypass of genetic constraints during mutator evolution to antibiotic resistance

2015

View full text Add to dashboard Cite

Genetic constraints can block many mutational pathways to optimal genotypes in real fitness landscapes, yet the extent to which this can limit evolution remains to be determined. Interestingly, mutator bacteria elevate only specific types of mutations, and therefore could be very sensitive to genetic constraints. Testing this possibility is not only clinically relevant, but can also inform about the general impact of genetic constraints in adaptation. Here, we evolved 576 populations of two mutator and one wild-type Escherichia coli to doubling concentrations of the antibiotic cefotaxime. All strains carried TEM-1, a b-lactamase enzyme well known by its low availability of mutational pathways. Crucially, one of the mutators does not elevate any of the relevant first-step mutations known to improve cefatoximase activity. Despite this, both mutators displayed a similar ability to evolve more than 1000-fold resistance. Initial adaptation proceeded in parallel through general multi-drug resistance mechanisms. High-level resistance, in contrast, was achieved through divergent paths; with the a priori inferior mutator exploiting alternative mutational pathways in PBP3, the target of the antibiotic. These results have implications for mutator management in clinical infections and, more generally, illustrate that limits to natural selection in real organisms are alleviated by the existence of multiple loci contributing to fitness.

show abstract

Section: Discussionsupporting

confidence: 81%

Bypass of genetic constraints during mutator evolution to antibiotic resistance

2015

View full text Add to dashboard Cite

show abstract

“…Bell & Foster, 1994). In microbes, parallel evolution is less well studied, although it is known to occur in the context of metronidazole resistance in Helicobacter pylori (Albert et al, 2005). However, the simple fact that we 'know' the genetic targets of resistance for the most commonly used antibiotics, and that these are highly conserved across species (for example, gyrA mutations confer resistance to quinolones, rpoB mutations confer resistance to rifampicin and so on), suggests that parallel evolution is a hallmark of resistance evolution.…”

Section: Parallel Evolution In Quinolone Resistancementioning

confidence: 99%

Parallel evolution and local differentiation in quinolone resistance in Pseudomonas aeruginosa

Wong

Kassen

2011

Microbiology

View full text Add to dashboard Cite

The emergence and spread of antibiotic resistance in pathogens is a major impediment to the control of microbial disease. Here, we review mechanisms of quinolone resistance in Pseudomonas aeruginosa, an important nosocomial pathogen and a major cause of morbidity in cystic fibrosis (CF) patients. In this quantitative literature review, we find that mutations in DNA gyrase A, the primary target of quinolones in Gram-negative bacteria, are the most common resistance mutations identified in clinical samples of all origins, in keeping with previous observations. However, the identities of non-gyrase resistance mutations vary systematically between samples isolated from CF patients and those isolated from acute infections. CF-derived strains tend to harbour mutations in the efflux pump regulator nfxB, while non-CF strains tend to bear mutations in the efflux regulator mexR or in parC, which encodes one of two subunits of DNA topoisomerase IV. We suggest that differences in resistance mechanisms between CF and non-CF strains result either from local adaptation to different sites of infection or from differences in mutational processes between different environments. We further discuss the therapeutic implications of local differentiation in resistance mechanisms to a common antibiotic.

show abstract

“…These results imply that allelic variation is a key contributor to the attenuated virulence observed for the carrier strains. To identify allelic variation that may contribute to the observed virulence phenotypes, we used a two-stage DNA-DNA microarray hybridization-based comparative genomic resequencing (CGR) method (22). These arrays, in conjunction with polymorphism sequencing, defined genome-wide all strain-tostrain differences in gene content (Fig.…”

Section: Identification Of Genetic Polymorphisms In Serotype M3 Strainsmentioning

confidence: 99%

Molecular genetic anatomy of inter- and intraserotype variation in the human bacterial pathogen group A Streptococcus

Beres

Richter

Nagiec

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

201

177

View full text Add to dashboard Cite

In recent years we have studied the relationship between strain genotypes and patient phenotypes in group A Streptococcus (GAS), a model human bacterial pathogen that causes extensive morbidity and mortality worldwide. We have concentrated our efforts on serotype M3 organisms because these strains are common causes of pharyngeal and invasive infections, produce unusually severe invasive infections, and can exhibit epidemic behavior. Our studies have been hindered by the lack of genome-scale phylogenies of multiple GAS strains and whole-genome sequences of multiple serotype M3 strains recovered from individuals with defined clinical phenotypes. To remove some of these impediments, we sequenced to closure the genome of four additional GAS strains and conducted comparative genomic resequencing of 12 contemporary serotype M3 strains representing distinct genotypes and phenotypes. Serotype M3 strains are a single phylogenetic lineage. Strains from asymptomatic throat carriers were significantly less virulent for mice than sterile-site isolates and evolved to a less virulent phenotype by multiple genetic pathways. Strain persistence or extinction between epidemics was strongly associated with presence or absence, respectively, of the prophage encoding streptococcal pyrogenic exotoxin A. A serotype M3 clone significantly underrepresented among necrotizing fasciitis cases has a unique frameshift mutation that truncates MtsR, a transcriptional regulator controlling expression of genes encoding ironacquisition proteins. Expression microarray analysis of this clone confirmed significant alteration in expression of genes encoding iron metabolism proteins. Our analysis provided unprecedented detail about the molecular anatomy of bacterial strain genotypepatient phenotype relationships.carrier ͉ epidemic ͉ genomic resequencing ͉ SNP ͉ phylogeny M icrobial epidemics have repeatedly altered the course of history by decimating human populations, killing domesticated animals, and blighting crops. Despite the impact of these destructive events, we know relatively little about the evolutionary genetic events contributing to bacterial strain emergence and diversification within and between epidemic waves. Also poorly understood is the molecular basis of intraspecies variation in disease phenotype. The recent confluence of genome sequencing and development of high-throughput techniques to interrogate genetic polymorphisms in large samples of strains now permits these topics to be studied at the individual nucleotide level.Group A Streptococcus (GAS) infects humans worldwide and causes an array of diseases ranging from superficial infections such as pharyngitis to fulminant invasive infections characterized by high morbidity and mortality (1, 2). In recent years, we have used serotype M3 GAS strains as model pathogens for studying the molecular processes contributing to clone emergence, epidemic waves, and genotype-phenotype relationships (M protein is a highly polymorphic cell-surface molecule that is antiphagocytic and forms the bas...

show abstract

Mutation discovery in bacterial genomes: metronidazole resistance in Helicobacter pylori

Cited by 185 publications

References 15 publications

Bypass of genetic constraints during mutator evolution to antibiotic resistance

Bypass of genetic constraints during mutator evolution to antibiotic resistance

Parallel evolution and local differentiation in quinolone resistance in Pseudomonas aeruginosa

Molecular genetic anatomy of inter- and intraserotype variation in the human bacterial pathogen group A Streptococcus

Contact Info

Product

Resources

About