scholarly journals The population genetics of collateral resistance and sensitivity

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Sarah M Ardell ◽  
Sergey Kryazhimskiy
Keyword(s):  
Joint Distribution ◽  
Resistance Mutations ◽  
Practical Applications ◽  
Collateral Sensitivity ◽  
Fitness Effects ◽  
Trade Offs ◽  
Variable Environments ◽  
Collateral Effects ◽  
Drug Treatments ◽  
Evolution Of Resistance

Resistance mutations against one drug can elicit collateral sensitivity against other drugs. Multi-drug treatments exploiting such trade-offs can help slow down the evolution of resistance. However, if mutations with diverse collateral effects are available, a treated population may evolve either collateral sensitivity or collateral resistance. How to design treatments robust to such uncertainty is unclear. We show that many resistance mutations in Escherichia coli against various antibiotics indeed have diverse collateral effects. We propose to characterize such diversity with a joint distribution of fitness effects (JDFE) and develop a theory for describing and predicting collateral evolution based on simple statistics of the JDFE. We show how to robustly rank drug pairs to minimize the risk of collateral resistance and how to estimate JDFEs. In addition to practical applications, these results have implications for our understanding of evolution in variable environments.

scholarly journals Allele-specific collateral and fitness effects determine the dynamics of fluoroquinolone-resistance evolution

2020 ◽  
Author(s):  
Apostolos Liakopoulos ◽  
Linda B. S. Aulin ◽  
Matteo Buffoni ◽  
J. G. Coen van Hasselt ◽  
Daniel E. Rozen
Keyword(s):  
Antibiotic Resistance ◽  
Combination Treatment ◽  
Evolutionary Dynamics ◽  
Fluoroquinolone Resistance ◽  
Resistant Bacteria ◽  
Resistance Mutations ◽  
Collateral Sensitivity ◽  
Resistance Evolution ◽  
Fitness Effects ◽  
Collateral Effects

AbstractCollateral sensitivity (CS), which arises when resistance to one antibiotic increases sensitivity towards other antibiotics, offers novel treatment opportunities to constrain or reverse the evolution of antibiotic resistance. The applicability of CS-informed treatments remains uncertain, in part because we lack an understanding of the generality of CS effects for different resistance mutations, singly or in combination. Here we address this issue in the Gram-positive pathogen S. pneumoniae by quantifying collateral and fitness effects of a series of clinically relevant first-step (gyrA or parC) mutations, and their combinations, that confer resistance to fluoroquinolones. We integrated these results in a mathematical model which allowed us to evaluate how different in silico combination treatments impact the dynamics of resistance evolution. We identified common and conserved CS effects of different gyrA and parC mutations; however, the spectrum of collateral effects was unique for each mutation or mutation pair. This indicated that mutation identity, even different mutations to the same amino acid, can impact the evolutionary dynamics of resistance evolution during monotreatment and combination treatment. In addition, we observed that epistatic effects between gyrA and parC mutations strongly alter the strength of collateral effects against different antibiotics. Our model simulations, which included the experimentally derived antibiotic susceptibilities and fitness effects, and antibiotic specific pharmacodynamics, revealed that both collateral and fitness effects impact the population dynamics of resistance evolution. Overall, we provide evidence that the gene, mutational identity, and interactions between resistance mutations can have a pronounced impact on collateral effects to different antibiotics and suggest that these need to be considered in models examining CS-based therapies.SignificanceA promising strategy to overcome the evolution of antibiotic resistant bacteria is to use collateral sensitivity-informed antibiotic treatments that rely on cycling or mixing of antibiotics, such that that resistance towards one antibiotic confers increased sensitivity to the other. Here, focusing on multi-step fluoroquinolone resistance in Streptococcus pneumoniae, we show that antibiotic-resistance induces diverse collateral responses, whose magnitude and direction are determined by mutation identity and epistasis between resistance mutations. Using mathematical simulations, we show that these effects can be exploited via combination treatment regimens to suppress the de novo emergence of resistance during treatment.

Fitness costs associated with field-evolved resistance to chlorantraniliprole inPlutella xylostella(Lepidoptera: Plutellidae)

2013 ◽  
Vol 104 (1) ◽  
pp. 88-96 ◽  
Author(s):  
L.M.S. Ribeiro ◽  
V. Wanderley-Teixeira ◽  
H.N. Ferreira ◽  
Á.A.C. Teixeira ◽  
H.A.A. Siqueira
Keyword(s):  
High Resistance ◽  
Egg Laying ◽  
Biological Parameters ◽  
Fitness Costs ◽  
Practical Applications ◽  
Trade Offs ◽  
Recent Estimate ◽  
Important Pest ◽  
Evolution Of Resistance ◽  
Resistant Strains

AbstractPlutella xylostella(L.) is the most important pest of Brassicaceae worldwide, with a recent estimate of US$ 4–5 billion expenditure for the control of this insect. A case of very high resistance of this pest to chlorantraniliprole was recently associated with reduced efficacy in a Brazilian field ofBrassicaspp. Although diamide resistance has been characterized, the fitness of insects due to such resistance has yet to be examined. Therefore, in this study, biological parameters were assessed in both susceptible and resistant strains ofP. xylostellasubjected to sublethal chlorantraniliprole concentrations. The field strain showed high resistance to chlorantraniliprole (RR50=27,793-fold), although resistance rapidly decreased in the first generations, showing instability. The exposure of susceptible and resistant larvae to their respective LC1, LC10, and LC25values led to an increased duration of the larval and pupae phases and reduced weight in both strains; however, no significant differences in pupal viability across the treatments were observed. The resistant insects presented significantly lower larval weight and fecundity and higher larval and pupal periods, hatchability, and male longevity when not exposed to chlorantraniliprole, suggesting a fitness cost associated with resistance. In addition, resistant females showed a significantly higher egg-laying period and longevity at LC25, whereas the males lived longer at LC1. Chlorantraniliprole negatively impacted the biological parameters of both strains tested, although these effects were more relevant to the resistant insects. ResistantP. xylostellashowed negative and positive biological trade-offs when compared with the susceptible individuals in both the absence and presence of chlorantraniliprole. Despite the important role that these trade-offs may play in the evolution of resistance to chlorantraniliprole, practical applications still depend on such information as the dominance of fitness costs and resistance.

scholarly journals Global patterns in genomic diversity underpinning the evolution of insecticide resistance in the aphid crop pest Myzus persicae

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Kumar Saurabh Singh ◽  
Erick M. G. Cordeiro ◽  
Bartlomiej J. Troczka ◽  
Adam Pym ◽  
Joanna Mackisack ◽  
...  
Keyword(s):  
Host Plant ◽  
Myzus Persicae ◽  
Resistance Mechanisms ◽  
Genomic Diversity ◽  
Resistance Mutations ◽  
Host Plant Adaptation ◽  
Repeated Evolution ◽  
Evolution Of Resistance ◽  
Selective Forces ◽  
Clonal Lines

AbstractThe aphid Myzus persicae is a destructive agricultural pest that displays an exceptional ability to develop resistance to both natural and synthetic insecticides. To investigate the evolution of resistance in this species we generated a chromosome-scale genome assembly and living panel of >110 fully sequenced globally sampled clonal lines. Our analyses reveal a remarkable diversity of resistance mutations segregating in global populations of M. persicae. We show that the emergence and spread of these mechanisms is influenced by host–plant associations, uncovering the widespread co‐option of a host-plant adaptation that also offers resistance against synthetic insecticides. We identify both the repeated evolution of independent resistance mutations at the same locus, and multiple instances of the evolution of novel resistance mechanisms against key insecticides. Our findings provide fundamental insights into the genomic responses of global insect populations to strong selective forces, and hold practical relevance for the control of pests and parasites.

scholarly journals A decision analysis framework for stakeholder involvement and learning in groundwater management

2013 ◽  
Vol 10 (7) ◽  
pp. 8747-8780 ◽  
Author(s):  
T. P. Karjalainen ◽  
P. M. Rossi ◽  
P. Ala-aho ◽  
R. Eskelinen ◽  
K. Reinikainen ◽  
...  
Keyword(s):  
Decision Analysis ◽  
Groundwater Management ◽  
Stakeholder Participation ◽  
Scientific Information ◽  
Stakeholder Involvement ◽  
Resource Planning ◽  
Assessment Process ◽  
Analysis Framework ◽  
Practical Applications ◽  
Trade Offs

Abstract. Multi-criteria decision analysis (MCDA) methods are increasingly used to facilitate both rigorous analysis and stakeholder involvement in natural and water resource planning. Decision making in that context is often complex and multi-faceted with numerous trade-offs between social, environmental and economic impacts. However, practical applications of decision-support methods are often too technically oriented and hard to use, understand or interpret for all participants. The learning of participants in these processes is seldom examined, even though successful deliberation depends on learning. This paper analyzes the potential of an interactive MCDA framework, the decision analysis interview (DAI) approach, for facilitating stakeholder involvement and learning in groundwater management. It evaluates the results of an MCDA process in assessing land-use management alternatives in a Finnish esker aquifer area where conflicting land uses affect the groundwater body and dependent ecosystems. In the assessment process, emphasis was placed on the interactive role of the MCDA tool in facilitating stakeholder participation and learning. The results confirmed that the structured decision analysis framework can foster learning and collaboration in a process where disputes and diverse interests are represented. Computer-aided interviews helped the participants to see how their preferences affected the desirability and ranking of alternatives. During the process, the participants' knowledge and preferences evolved as they assess their initial knowledge with the help of fresh scientific information. The decision analysis process led to the opening of a dialogue, showing the overall picture of the problem context, and the critical issues for the further process.

scholarly journals Fitness Trade-Offs in blaTEM Evolution

2008 ◽  
Vol 52 (7) ◽  
pp. 2340-2345 ◽  
Author(s):  
Joanna E. Mroczkowska ◽  
Miriam Barlow
Keyword(s):  
Microbial Populations ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Bacterial Populations ◽  
Real Time Quantitative Pcr ◽  
Fitness Effects ◽  
Fitness Advantage ◽  
Extended Spectrum ◽  
Trade Offs ◽  
Pcr Method

ABSTRACT bla TEM-1 expression results in penicillin resistance, whereas expression of many bla TEM-1 descendants, called extended-spectrum β-lactamases (ESBLs), results simultaneously in resistance to penicillins and extended-spectrum cephalosporins. Despite the expanded resistance phenotypes conferred by many ESBLs, bla TEM-1 is still the most abundant bla TEM allele in many microbial populations. This study examines the fitness effects of the two amino acid substitutions, R164S and E240K, that have occurred repeatedly among ESBL bla TEM-1 descendants. Using a single-nucleotide polymorphism-specific real-time quantitative PCR method, we analyzed the fitness of strains expressing bla TEM-1, bla TEM-10, and bla TEM-12. Our results show that bacteria expressing the ancestral bla TEM-1 allele have a fitness advantage over those expressing either bla TEM-10 or bla TEM-12 when exposed to ampicillin. This observation, combined with the fact that penicillins are the most prevalent antimicrobials prescribed worldwide, may explain why bla TEM-1 has persisted as the most frequently encountered bla TEM allele in bacterial populations.

scholarly journals Increased Survival of Antibiotic-Resistant Escherichia coli inside Macrophages

2012 ◽  
Vol 57 (1) ◽  
pp. 189-195 ◽  
Author(s):  
Migla Miskinyte ◽  
Isabel Gordo
Keyword(s):  
Escherichia Coli ◽  
Antibiotic Resistance ◽  
Bacterial Infections ◽  
Resistance Mutation ◽  
Fitness Cost ◽  
Resistance Mutations ◽  
Content Type ◽  
E Coli ◽  
Fitness Effects ◽  
K 12

ABSTRACTMutations causing antibiotic resistance usually incur a fitness cost in the absence of antibiotics. The magnitude of such costs is known to vary with the environment. Little is known about the fitness effects of antibiotic resistance mutations when bacteria confront the host's immune system. Here, we study the fitness effects of mutations in therpoB,rpsL, andgyrAgenes, which confer resistance to rifampin, streptomycin, and nalidixic acid, respectively. These antibiotics are frequently used in the treatment of bacterial infections. We measured two important fitness traits—growth rate and survival ability—of 12Escherichia coliK-12 strains, each carrying a single resistance mutation, in the presence of macrophages. Strikingly, we found that 67% of the mutants survived better than the susceptible bacteria in the intracellular niche of the phagocytic cells. In particular, allE. colistreptomycin-resistant mutants exhibited an intracellular advantage. On the other hand, 42% of the mutants incurred a high fitness cost when the bacteria were allowed to divide outside of macrophages. This study shows that single nonsynonymous changes affecting fundamental processes in the cell can contribute to prolonged survival ofE. coliin the context of an infection.

scholarly journals Using Selection by Nonantibiotic Stressors to Sensitize Bacteria to Antibiotics

2019 ◽  
Vol 37 (5) ◽  
pp. 1394-1406 ◽  
Author(s):  
Jeff Maltas ◽  
Brian Krasnick ◽  
Kevin B Wood
Keyword(s):  
Osmotic Stress ◽  
Drug Targets ◽  
Bacterial Pathogen ◽  
Multidrug Efflux ◽  
Collateral Sensitivity ◽  
Environmental Agents ◽  
Collateral Effects ◽  
Selective Forces ◽  
Increased Sensitivity ◽  
Multiple Antibiotics

Abstract Evolutionary adaptation of bacteria to nonantibiotic selective forces, such as osmotic stress, has been previously associated with increased antibiotic resistance, but much less is known about potentially sensitizing effects of nonantibiotic stressors. In this study, we use laboratory evolution to investigate adaptation of Enterococcus faecalis, an opportunistic bacterial pathogen, to a broad collection of environmental agents, ranging from antibiotics and biocides to extreme pH and osmotic stress. We find that nonantibiotic selection frequently leads to increased sensitivity to other conditions, including multiple antibiotics. Using population sequencing and whole-genome sequencing of single isolates from the evolved populations, we identify multiple mutations in genes previously linked with resistance to the selecting conditions, including genes corresponding to known drug targets or multidrug efflux systems previously tied to collateral sensitivity. Finally, we hypothesized based on the measured sensitivity profiles that sequential rounds of antibiotic and nonantibiotic selection may lead to hypersensitive populations by harnessing the orthogonal collateral effects of particular pairs of selective forces. To test this hypothesis, we show experimentally that populations evolved to a sequence of linezolid (an oxazolidinone antibiotic) and sodium benzoate (a common preservative) exhibit increased sensitivity to more stressors than adaptation to either condition alone. The results demonstrate how sequential adaptation to drug and nondrug environments can be used to sensitize bacteria to antibiotics and highlight new potential strategies for exploiting shared constraints governing adaptation to diverse environmental challenges.

scholarly journals OXA-48-Mediated Ceftazidime-Avibactam Resistance Is Associated with Evolutionary Trade-Offs

mSphere ◽  
2019 ◽  
Vol 4 (2) ◽  
Author(s):  
Christopher Fröhlich ◽  
Vidar Sørum ◽  
Ane Molden Thomassen ◽  
Pål Jarle Johnsen ◽  
Hanna-Kirsti S. Leiros ◽  
...  
Keyword(s):  
Amino Acid ◽  
Inhibitory Activity ◽  
Treatment Options ◽  
Inhibitory Effect ◽  
Amino Acid Substitutions ◽  
Gram Negative ◽  
Content Type ◽  
Mortality And Morbidity ◽  
Trade Offs ◽  
Collateral Effects

ABSTRACTInfections due to carbapenemase-producing Gram-negative pathogens are associated with limited treatment options and consequently lead to increased mortality and morbidity. In response, combinations of existing β-lactams and novel β-lactamase inhibitors, such as ceftazidime-avibactam (CAZ-AVI), have been developed as alternative treatment options. To understand the development of resistance and evolutionary trajectories under CAZ-AVI exposure, we studied the effects of ceftazidime (CAZ) and CAZ-AVI on the carbapenemase OXA-48 and the epidemic OXA-48 plasmid inEscherichia coli. Exposure of CAZ and CAZ-AVI resulted in single (P68A) and double (P68A,Y211S) amino acid substitutions in OXA-48, respectively. The antimicrobial susceptibility data and enzyme kinetics showed that the P68A substitution was responsible for an increased activity toward CAZ, whereas P68A,Y211S led to a decrease in the inhibitory activity of AVI. X-ray crystallography and molecular modeling of the mutants demonstrated increased flexibility within the active site, which could explain the elevated CAZ hydrolysis and reduced inhibitory activity of AVI. Interestingly, these substitutions resulted in collateral effects compromising the activity of OXA-48 toward carbapenems and penicillins. Moreover, exposure to CAZ-AVI selected for mutations within the OXA-48-encoding plasmid that severely reduced fitness in the absence of antimicrobial selection. These evolutionary trade-offs may contribute to limit the evolution of OXA-48-mediated CAZ and CAZ-AVI resistance, as well as potentially resensitize isolates toward other therapeutic alternatives.IMPORTANCEThe recent introduction of novel β-lactam/β-lactamase inhibitor combinations like ceftazidime-avibactam has increased our ability to treat infections caused by multidrug-resistant Gram-negative bacteria, including carbapenemase-producingEnterobacterales. However, the increasing number of cases of reported resistance to ceftazidime-avibactam is a concern. OXA-48 is a carbapenemase that has no significant effect on ceftazidime, but is inhibited by avibactam. Since isolates with OXA-48 frequently harbor extended-spectrum β-lactamases that are inhibited by avibactam, it is likely that ceftazidime-avibactam will be used to treat infections caused by OXA-48-producingEnterobacterales.Our data show that exposure to ceftazidime-avibactam can lead to changes in OXA-48, resulting in increased ability to hydrolyze ceftazidime and withstand the inhibitory effect of avibactam. Thus, resistance toward ceftazidime-avibactam among OXA-48-producingEnterobacteralesshould be monitored. Interestingly, the compromising effect of the amino acid substitutions in OXA-48 on other β-lactams and the effect of ceftazidime-avibactam exposure on the epidemic OXA-48 plasmid indicate that the evolution of ceftazidime-avibactam resistance comes with collateral effects.

scholarly journals Evolution of the Insecticide Target Rdl in African Anopheles Is Driven by Interspecific and Interkaryotypic Introgression

2020 ◽  
Vol 37 (10) ◽  
pp. 2900-2917 ◽  
Author(s):  
Xavier Grau-Bové ◽  
Sean Tomlinson ◽  
Andrias O O’Reilly ◽  
Nicholas J Harding ◽  
Alistair Miles ◽  
...  
Keyword(s):  
Large Scale ◽  
Sequence Data ◽  
Management Strategies ◽  
Natural Populations ◽  
Resistance Mechanisms ◽  
Health Concern ◽  
Malaria Vectors ◽  
Resistance Mutations ◽  
Development Of Resistance ◽  
Evolution Of Resistance

Abstract The evolution of insecticide resistance mechanisms in natural populations of Anopheles malaria vectors is a major public health concern across Africa. Using genome sequence data, we study the evolution of resistance mutations in the resistance to dieldrin locus (Rdl), a GABA receptor targeted by several insecticides, but most notably by the long-discontinued cyclodiene, dieldrin. The two Rdl resistance mutations (296G and 296S) spread across West and Central African Anopheles via two independent hard selective sweeps that included likely compensatory nearby mutations, and were followed by a rare combination of introgression across species (from A. gambiae and A. arabiensis to A. coluzzii) and across nonconcordant karyotypes of the 2La chromosomal inversion. Rdl resistance evolved in the 1950s as the first known adaptation to a large-scale insecticide-based intervention, but the evolutionary lessons from this system highlight contemporary and future dangers for management strategies designed to combat development of resistance in malaria vectors.

scholarly journals Limited Evolutionary Conservation of the Phenotypic Effects of Antibiotic Resistance Mutations

2019 ◽  
Vol 36 (8) ◽  
pp. 1601-1611 ◽  
Author(s):  
Gábor Apjok ◽  
Gábor Boross ◽  
Ákos Nyerges ◽  
Gergely Fekete ◽  
Viktória Lázár ◽  
...  
Keyword(s):  
Drug Hypersensitivity ◽  
Bacterial Species ◽  
Treatment Strategies ◽  
Specific Treatment ◽  
Resistant Bacteria ◽  
Resistance Mutations ◽  
Aminoglycoside Resistance ◽  
Collateral Sensitivity ◽  
Depth Analysis ◽  
Species Specific

AbstractMultidrug-resistant clinical isolates are common in certain pathogens, but rare in others. This pattern may be due to the fact that mutations shaping resistance have species-specific effects. To investigate this issue, we transferred a range of resistance-conferring mutations and a full resistance gene into Escherichia coli and closely related bacteria. We found that resistance mutations in one bacterial species frequently provide no resistance, in fact even yielding drug hypersensitivity in close relatives. In depth analysis of a key gene involved in aminoglycoside resistance (trkH) indicated that preexisting mutations in other genes—intergenic epistasis—underlie such extreme differences in mutational effects between species. Finally, reconstruction of adaptive landscapes under multiple antibiotic stresses revealed that mutations frequently provide multidrug resistance or elevated drug susceptibility (i.e., collateral sensitivity) only with certain combinations of other resistance mutations. We conclude that resistance and collateral sensitivity are contingent upon the genetic makeup of the bacterial population, and such contingency could shape the long-term fate of resistant bacteria. These results underlie the importance of species-specific treatment strategies.

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