scholarly journals Choice of β-lactam resistance pathway depends critically on initial antibiotic concentration

2021 ◽  
Author(s):  
Philip Ruelens ◽  
J. Arjan G.M. de Visser
Keyword(s):  
Antibiotic Resistance ◽  
Mutation Bias ◽  
Antibiotic Concentration ◽  
Epistatic Interactions ◽  
Low Resistance ◽  
Resistance Evolution ◽  
Fitness Effects ◽  
Resistance Pathway

Antibiotic-resistance trajectories with different final resistance may critically depend on the first mutation due to epistatic interactions. Here, we study the effect of mutation bias and concentration-dependent fitness effects of two clinically important mutations in TEM-1 β-lactamase initiating alternative trajectories to cefotaxime resistance. We show that mutation R164S, conferring relatively low resistance, is competitively superior over larger-effect mutation G238S at low cefotaxime concentrations, highlighting a critical influence of antibiotic concentration on long-term resistance evolution.

scholarly journals Antibiotic Resistance Evolution Is Contingent on the Quorum-Sensing Response in Pseudomonas aeruginosa

2019 ◽  
Vol 36 (10) ◽  
pp. 2238-2251 ◽  
Author(s):  
Sara Hernando-Amado ◽  
Fernando Sanz-García ◽  
José Luis Martínez
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antibiotic Resistance ◽  
Quorum Sensing ◽  
Wild Type ◽  
Resistance Mutations ◽  
Epistatic Interactions ◽  
Adaptive Mutations ◽  
Resistance Evolution ◽  
Evolutionary Trajectories

Abstract Different works have explored independently the evolution toward antibiotic resistance and the role of eco-adaptive mutations in the adaptation to a new habitat (as the infected host) of bacterial pathogens. However, knowledge about the connection between both processes is still limited. We address this issue by comparing the evolutionary trajectories toward antibiotic resistance of a Pseudomonas aeruginosa lasR defective mutant and its parental wild-type strain, when growing in presence of two ribosome-targeting antibiotics. Quorum-sensing lasR defective mutants are selected in P. aeruginosa populations causing chronic infections. Further, we observed they are also selected in vitro as a first adaptation for growing in culture medium. By using experimental evolution and whole-genome sequencing, we found that the evolutionary trajectories of P. aeruginosa in presence of these antibiotics are different in lasR defective and in wild-type backgrounds, both at the phenotypic and the genotypic levels. Recreation of a set of mutants in both genomic backgrounds (either wild type or lasR defective) allowed us to determine the existence of negative epistatic interactions between lasR and antibiotic resistance determinants. These epistatic interactions could lead to mutual contingency in the evolution of antibiotic resistance when P. aeruginosa colonizes a new habitat in presence of antibiotics. If lasR mutants are selected first, this would constraint antibiotic resistance evolution. Conversely, when resistance mutations (at least those studied in the present work) are selected, lasR mutants may not be selected in presence of antibiotics. These results underlie the importance of contingency and epistatic interactions in modulating antibiotic resistance evolution.

scholarly journals A trimethoprim derivative impedes antibiotic resistance evolution

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Madhu Sudan Manna ◽  
Yusuf Talha Tamer ◽  
Ilona Gaszek ◽  
Nicole Poulides ◽  
Ayesha Ahmed ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Resistant Bacteria ◽  
Gene Encoding ◽  
Antibiotic Resistant ◽  
E Coli ◽  
Resistance Evolution ◽  
Evolutionary Trajectories ◽  
Evolution Of Resistance

AbstractThe antibiotic trimethoprim (TMP) is used to treat a variety of Escherichia coli infections, but its efficacy is limited by the rapid emergence of TMP-resistant bacteria. Previous laboratory evolution experiments have identified resistance-conferring mutations in the gene encoding the TMP target, bacterial dihydrofolate reductase (DHFR), in particular mutation L28R. Here, we show that 4’-desmethyltrimethoprim (4’-DTMP) inhibits both DHFR and its L28R variant, and selects against the emergence of TMP-resistant bacteria that carry the L28R mutation in laboratory experiments. Furthermore, antibiotic-sensitive E. coli populations acquire antibiotic resistance at a substantially slower rate when grown in the presence of 4’-DTMP than in the presence of TMP. We find that 4’-DTMP impedes evolution of resistance by selecting against resistant genotypes with the L28R mutation and diverting genetic trajectories to other resistance-conferring DHFR mutations with catalytic deficiencies. Our results demonstrate how a detailed characterization of resistance-conferring mutations in a target enzyme can help identify potential drugs against antibiotic-resistant bacteria, which may ultimately increase long-term efficacy of antimicrobial therapies by modulating evolutionary trajectories that lead to resistance.

scholarly journals Epistasis between antibiotic resistance mutations and genetic background shape the fitness effect of resistance across species of Pseudomonas

2016 ◽  
Vol 283 (1830) ◽  
pp. 20160151 ◽  
Author(s):  
T. Vogwill ◽  
M. Kojadinovic ◽  
R. C. MacLean
Keyword(s):  
Antibiotic Resistance ◽  
Resistance Mutations ◽  
Bacterial Strains ◽  
Fitness Effect ◽  
Epistatic Interactions ◽  
Fitness Effects ◽  
Cost Of Resistance ◽  
Pathogen Populations ◽  
The Cost ◽  
Antibiotic Resistance Mutations

Antibiotic resistance often evolves by mutations at conserved sites in essential genes, resulting in parallel molecular evolution between divergent bacterial strains and species. Whether these resistance mutations are having parallel effects on fitness across bacterial taxa, however, is unclear. This is an important point to address, because the fitness effects of resistance mutations play a key role in the spread and maintenance of resistance in pathogen populations. We address this idea by measuring the fitness effect of a collection of rifampicin resistance mutations in the β subunit of RNA polymerase ( rpoB ) across eight strains that span the diversity of the genus Pseudomonas . We find that almost 50% of rpoB mutations have background-dependent fitness costs, demonstrating that epistatic interactions between rpoB and the rest of the genome are common. Moreover, epistasis is typically strong, and it is the dominant genetic determinant of the cost of resistance mutations. To investigate the functional basis of epistasis, and because rpoB plays a central role in transcription, we measured the effects of common rpoB mutations on transcriptional efficiency across three strains of Pseudomonas . Transcriptional efficiency correlates strongly to fitness across strains, and epistasis arises because individual rpoB mutations have differential effects on transcriptional efficiency in different genetic backgrounds.

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.

scholarly journals Antibiotic breakdown by susceptible bacteria enhances the establishment of β-lactam resistant mutants

2021 ◽  
Author(s):  
Manja Saebelfeld ◽  
Suman G Das ◽  
Jorn Brink ◽  
Arno Hagenbeek ◽  
Joachim Krug ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Antibiotic Resistance ◽  
Theoretical Model ◽  
Enzymatic Activity ◽  
Social Interactions ◽  
Single Cells ◽  
Antibiotic Concentration ◽  
High Frequencies ◽  
Establishment Probability ◽  
Resistant Mutants

For a better understanding of the evolution of antibiotic resistance, it is imperative to study the factors that determine the initial establishment of mutant resistance alleles. In addition to the antibiotic concentration, the establishment of resistance alleles may be affected by interactions with the surrounding susceptible cells from which they derive, for instance via the release of nutrients or removal of the antibiotic. Here, we investigate the effects of social interactions with surrounding susceptible cells on the establishment of Escherichia coli mutants with increasing β-lactamase activity (i.e. the capacity to hydrolyze β-lactam antibiotics) from single cells under the exposure of the antibiotic cefotaxime on agar plates. We find that mutant establishment probability is increased in the presence of susceptible cells due to the active breakdown of the antibiotic, but the rate of breakdown by the susceptible strain is much higher than expected based on its low enzymatic activity. A detailed theoretical model suggests that this observation can be explained by cell filamentation causing delayed lysis. While susceptible cells may hamper the spread of higher-resistant β-lactamase mutants at relatively high frequencies, our findings show that they could promote establishment during their emergence.

scholarly journals Molecular function limits divergent protein evolution on planetary timescales

2017 ◽  
Author(s):  
Mariam M. Konaté ◽  
Germán Plata ◽  
Jimin Park ◽  
Dinara R. Usmanova ◽  
Harris H. Wang ◽  
...  
Keyword(s):  
Amino Acid ◽  
Protein Evolution ◽  
Molecular Function ◽  
Functional Conservation ◽  
Fitness Effects ◽  
Sequence Identity ◽  
The Past ◽  
Independent Evolution

AbstractFunctional conservation is known to constrain protein evolution. Nevertheless, the long-term divergence patterns of proteins maintaining the same molecular function and the possible limits of this divergence have not been explored in detail. We investigate these fundamental questions by characterizing the divergence between ancient protein orthologs with conserved molecular function. Our results demonstrate that the decline of sequence and structural similarities between such orthologs significantly slows down after ~1-2 billion years of independent evolution. As a result, their sequence and structural similarities have not substantially decreased for the past billion years. The effective divergence limit (>25% sequence identity) is not primarily due to protein sites universally conserved in all linages. Instead, less than four amino acid types are accepted, on average, per site in orthologs strictly conserving their molecular function. Our analysis also reveals different divergence patterns for protein sites with experimentally determined small and large fitness effects of mutations.

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