scholarly journals Radial Expansion Facilitates the Maintenance of Double Antibiotic Resistances

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
Paulo Durão ◽  
Ricardo S. Ramiro ◽  
Cátia Pereira ◽  
Jernej Jurič ◽  
Delfina Pereira ◽  
...  
Keyword(s):  
Spatial Structure ◽  
Compensatory Mutation ◽  
Radial Expansion ◽  
Resistance Mutations ◽  
Bacterial Populations ◽  
Heterogeneous Distribution ◽  
Content Type ◽  
Local Competition ◽  
The One ◽  
Antibiotic Resistance Mutations

ABSTRACT Most microbes live in spatially confined subpopulations. Under spatial structure conditions, the efficacy of natural selection is often reduced (relative to homogeneous conditions) due to the increased importance of genetic drift and local competition. Additionally, under spatial structure conditions, the fittest genotype may not always be the one with better access to the heterogeneous distribution of nutrients. The effect of radial expansion may be particularly relevant for the elimination of antibiotic resistance mutations, as their dynamics within bacterial populations are strongly dependent on their growth rate. Here, we use Escherichia coli to systematically compare the allele frequency of streptomycin, rifampin, and fluoroquinolone single and double resistance mutants after 24 h of coexistence with a susceptible strain under radial expansion (local competition) and homogeneous (global competition) conditions. We show that there is a significant effect of structure on the maintenance of double resistances which is not observed for single resistances. Radial expansion also facilitates the persistence of double resistances when competing against their single counterparts. Importantly, we found that spatial structure reduces the rate of compensation of the double mutant RpsLK43T RpoBH526Y and that a strongly compensatory mutation in homogeneous conditions becomes deleterious under spatial structure conditions. Overall, our results unravel the importance of spatial structure for facilitating the maintenance and accumulation of multiple resistances over time and for determining the identity of compensatory mutations.

scholarly journals Phenotypic Suppression of Streptomycin Resistance by Mutations in Multiple Components of the Translation Apparatus

2015 ◽  
Vol 197 (18) ◽  
pp. 2981-2988 ◽  
Author(s):  
Jennifer F. Carr ◽  
Hannah J. Lee ◽  
Joshua B. Jaspers ◽  
Albert E. Dahlberg ◽  
Gerwald Jogl ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Long Range ◽  
Experimental Evolution ◽  
Thermus Thermophilus ◽  
Thermophilic Bacterium ◽  
Streptomycin Resistance ◽  
Resistance Mutations ◽  
Content Type ◽  
Translation Apparatus ◽  
Antibiotic Resistance Mutations

ABSTRACTThe bacterial ribosome and its associated translation factors are frequent targets of antibiotics, and antibiotic resistance mutations have been found in a number of these components. Such mutations can potentially interact with one another in unpredictable ways, including the phenotypic suppression of one mutation by another. These phenotypic interactions can provide evidence of long-range functional interactions throughout the ribosome and its functional complexes and potentially give insights into antibiotic resistance mechanisms. In this study, we used genetics and experimental evolution of the thermophilic bacteriumThermus thermophilusto examine the ability of mutations in various components of the protein synthesis apparatus to suppress the streptomycin resistance phenotypes of mutations in ribosomal protein S12, specifically those located distant from the streptomycin binding site. With genetic selections and strain constructions, we identified suppressor mutations in EF-Tu or in ribosomal protein L11. Using experimental evolution, we identified amino acid substitutions in EF-Tu or in ribosomal proteins S4, S5, L14, or L19, some of which were found to also relieve streptomycin resistance. The wide dispersal of these mutations is consistent with long-range functional interactions among components of the translational machinery and indicates that streptomycin resistance can result from the modulation of long-range conformational signals.IMPORTANCEThe thermophilic bacteriumThermus thermophilushas become a model system for high-resolution structural studies of macromolecular complexes, such as the ribosome, while its natural competence for transformation facilitates genetic approaches. Genetic studies ofT. thermophilusribosomes can take advantage of existing high-resolution crystallographic information to allow a structural interpretation of phenotypic interactions among mutations. Using a combination of genetic selections, strain constructions, and experimental evolution, we find that certain mutations in the translation apparatus can suppress the phenotype of certain antibiotic resistance mutations. Suppression of resistance can occur by mutations located distant in the ribosome or in a translation factor. These observations suggest the existence of long-range conformational signals in the translating ribosome, particularly during the decoding of mRNA.

scholarly journals Predictable Phenotypes of Antibiotic Resistance Mutations

mBio ◽  
2018 ◽  
Vol 9 (3) ◽  
Author(s):  
M. Knopp ◽  
D. I. Andersson
Keyword(s):  
Antibiotic Resistance ◽  
Resistant Bacteria ◽  
Resistance Mutations ◽  
Resistance Level ◽  
Epistatic Interactions ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Evolutionary Success ◽  
Antibiotic Resistance Mutations ◽  
Host Strains

ABSTRACTAntibiotic-resistant bacteria represent a major threat to our ability to treat bacterial infections. Two factors that determine the evolutionary success of antibiotic resistance mutations are their impact on resistance level and the fitness cost. Recent studies suggest that resistance mutations commonly show epistatic interactions, which would complicate predictions of their stability in bacterial populations. We analyzed 13 different chromosomal resistance mutations and 10 host strains ofSalmonella entericaandEscherichia colito address two main questions. (i) Are there epistatic interactions between different chromosomal resistance mutations? (ii) How does the strain background and genetic distance influence the effect of chromosomal resistance mutations on resistance and fitness? Our results show that the effects of combined resistance mutations on resistance and fitness are largely predictable and that epistasis remains rare even when up to four mutations were combined. Furthermore, a majority of the mutations, especially target alteration mutations, demonstrate strain-independent phenotypes across different species. This study extends our understanding of epistasis among resistance mutations and shows that interactions between different resistance mutations are often predictable from the characteristics of the individual mutations.IMPORTANCEThe spread of antibiotic-resistant bacteria imposes an urgent threat to public health. The ability to forecast the evolutionary success of resistant mutants would help to combat dissemination of antibiotic resistance. Previous studies have shown that the phenotypic effects (fitness and resistance level) of resistance mutations can vary substantially depending on the genetic context in which they occur. We conducted a broad screen using many different resistance mutations and host strains to identify potential epistatic interactions between various types of resistance mutations and to determine the effect of strain background on resistance phenotypes. Combinations of several different mutations showed a large amount of phenotypic predictability, and the majority of the mutations displayed strain-independent phenotypes. However, we also identified a few outliers from these patterns, illustrating that the choice of host organism can be critically important when studying antibiotic resistance mutations.

scholarly journals The DnaK Chaperone System Buffers the Fitness Cost of Antibiotic Resistance Mutations in Mycobacteria

mBio ◽  
2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Allison Fay ◽  
John Philip ◽  
Priya Saha ◽  
Ronald C. Hendrickson ◽  
Michael S. Glickman ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Causative Agent ◽  
Mycobacterium Smegmatis ◽  
Drug Targets ◽  
Genomic Diversity ◽  
Resistance Mutations ◽  
Content Type ◽  
Protein Chaperones ◽  
Antibiotic Resistance Mutations

ABSTRACT Chaperones aid in protein folding and maintenance of protein integrity. In doing so, they have the unique ability to directly stabilize resistance-conferring amino acid substitutions in drug targets and to counter the stress imparted by these substitutions, thus supporting heritable antimicrobial resistance (AMR). We asked whether chaperones support AMR in Mycobacterium smegmatis, a saprophytic model of Mycobacterium tuberculosis, the causative agent of tuberculosis (TB). We show that DnaK associates with many drug targets and that DnaK associates more with AMR-conferring mutant RNA polymerase (RNAP) than with wild-type RNAP. In addition, frequency-of-resistance (FOR) and fitness studies reveal that the DnaK system of chaperones supports AMR in antimicrobial targets in mycobacteria, including RNAP and the ribosome. These findings highlight chaperones as potential targets for drugs to overcome AMR in mycobacteria, including M. tuberculosis, as well as in other pathogens. IMPORTANCE AMR is a global problem, especially for TB. Here, we show that mycobacterial chaperones support AMR in M. smegmatis, a nonpathogenic model of M. tuberculosis, the causative agent of TB. In particular, the mycobacterial DnaK system of chaperones supports AMR in the antimicrobial targets RNA polymerase and the ribosome. This is the first report showing a role for protein chaperones in mediating AMR in mycobacteria. Given the widespread role of protein chaperones in enabling genomic diversity, we anticipate that our findings can be extended to other microbes.

How Phillips saw the light

2020 ◽  
Vol 36 (8) ◽  
pp. 29-31
Keyword(s):  
Design Methodology ◽  
Reading Time ◽  
Daily Basis ◽  
Business World ◽  
Content Type ◽  
Freak Show ◽  
The World ◽  
Pertinent Information ◽  
The One ◽  
Practical Implications

Purpose Reviews the latest management developments across the globe and pinpoints practical implications from cutting-edge research and case studies. Design/methodology/approach This briefing is prepared by an independent writer who adds their own impartial comments and places the articles in context. Findings The problem with developing a reputation of being something of an oracle in the business world is that all of a sudden, everyone expects you to pull off the trick of interpreting the future on a daily basis. Like a freak show circus act or one-hit wonder pop singer, people expect you to perform when they see you, and they expect you to perform the thing that made you famous, even if it is the one thing in the world you don’t want to do. And when you fail to deliver on these heightened expectations, you are dismissed as a one trick pony, however good that trick is in the first place. Originality/value The briefing saves busy executives and researchers hours of reading time by selecting only the very best, most pertinent information and presenting it in a condensed and easy-to-digest format.

PROMETHEE-based ranking of project managers based on the five personality traits

Kybernetes ◽  
2019 ◽  
Vol 49 (4) ◽  
pp. 1083-1102
Author(s):  
Georgios N. Aretoulis ◽  
Jason Papathanasiou ◽  
Fani Antoniou
Keyword(s):  
Personality Traits ◽  
Questionnaire Survey ◽  
Multicriteria Decision Making ◽  
Project Managers ◽  
Preference Ranking ◽  
Infrastructure Projects ◽  
Public Infrastructure ◽  
Content Type ◽  
The One ◽  
Selection Of

Purpose This paper aims to rank and identify the most efficient project managers (PMs) based on personality traits, using Preference Ranking Organization METHod for Enrichment Evaluations (PROMETHEE) methodology. Design/methodology/approach The proposed methodology relies on the five personality traits. These were used as the selection criteria. A questionnaire survey among 82 experienced engineers was used to estimate the required weights per personality trait. A second two-part questionnaire survey aimed at recording the PMs profile and assess the performance of personality traits per PM. PMs with the most years of experience are selected to be ranked through Visual PROMETHEE. Findings The findings suggest that a competent PM is the one that scores low on the “Neuroticism” trait and high especially on the “Conscientiousness” trait. Research limitations/implications The research applied a psychometric test specifically designed for Greek people. Furthermore, the proposed methodology is based on the personality characteristics to rank the PMs and does not consider the technical skills. Furthermore, the type of project is not considered in the process of ranking PMs. Practical implications The findings could contribute in the selection of the best PM that maximizes the project team’s performance. Social implications Improved project team communication and collaboration leading to improved project performance through better communication and collaboration. This is an additional benefit for the society, especially in the delivery of public infrastructure projects. A lot of public infrastructure projects deviate largely as far as cost and schedule is concerned and this is an additional burden for public and society. Proper project management through efficient PMs would save people’s money and time. Originality/value Identification of the best PMbased on a combination of multicriteria decision-making and psychometric tests, which focus on personality traits.

scholarly journals Beyond agency and stewardship theory: shareholder–manager relationships and governance structures in family firms

2020 ◽  
Vol ahead-of-print (ahead-of-print) ◽  
Author(s):  
Ann Sophie K. Löhde ◽  
Giovanna Campopiano ◽  
Andrea Calabrò
Keyword(s):  
Social Exchange ◽  
Family Business ◽  
Social Exchange Theory ◽  
Family Firms ◽  
Governance Structure ◽  
Managerial Behavior ◽  
Exchange System ◽  
Content Type ◽  
The One ◽  
Over Time

PurposeChallenging the static view of family business governance, we propose a model of owner–manager relationships derived from the configurational analysis of managerial behavior and change in governance structure.Design/methodology/approachStemming from social exchange theory and building on the 4C model proposed by Miller and Le Breton-Miller (2005), we consider the evolving owner–manager relationship in four main configurations. On the one hand, we account for family businesses shifting from a generalized to a restricted exchange system, and vice versa, according to whether a family manager misbehaves in a stewardship-oriented governance structure or a nonfamily manager succeeds in building a trusting relationship in an agency-oriented governance structure. On the other hand, we consider that family firms will strengthen a generalized exchange system, rather than a restricted one, according to whether a family manager contributes to the stewardship-oriented culture in the business or a nonfamily manager proves to be driven by extrinsic rewards. Four scenarios are analyzed in terms of the managerial behavior and governance structure that characterize the phases of the relationship between owners and managers.FindingsVarious factors trigger managerial behavior, making the firm deviate from or further build on what is assumed by stewardship and agency theories (i.e. proorganizational versus opportunistic behavior, respectively), which determine the governance structure over time. Workplace deviance, asymmetric altruism and patriarchy on the one hand, and proorganizational behavior, relationship building and long-term commitment on the other, are found to determine how the manager behaves and thus characterize the owner's reactions in terms of governance mechanisms. This enables us to present a dynamic view of governance structures, which adapt to the actual attitudes and behaviors of employed managers.Research limitations/implicationsAs time is a relevant dimension affecting individual behavior and triggering change in an organization, one must consider family business governance as being dynamic in nature. Moreover, it is not family membership that determines the most appropriate governance structure but the owner–manager relationship that evolves over time, thus contributing to the 4C model.Originality/valueThe proposed model integrates social exchange theory and the 4C model to predict changes in governance structure, as summarized in the final framework we propose.

scholarly journals Stochasticity in Colonial Growth Dynamics of Individual Bacterial Cells

2013 ◽  
Vol 79 (7) ◽  
pp. 2294-2301 ◽  
Author(s):  
Konstantinos P. Koutsoumanis ◽  
Alexandra Lianou
Keyword(s):  
Kinetic Parameters ◽  
Single Cells ◽  
Growth Curves ◽  
Growth Dynamics ◽  
Time Lapse ◽  
Initial Population ◽  
Bacterial Cells ◽  
Stochastic Growth ◽  
Bacterial Populations ◽  
Content Type

ABSTRACTConventional bacterial growth studies rely on large bacterial populations without considering the individual cells. Individual cells, however, can exhibit marked behavioral heterogeneity. Here, we present experimental observations on the colonial growth of 220 individual cells ofSalmonella entericaserotype Typhimurium using time-lapse microscopy videos. We found a highly heterogeneous behavior. Some cells did not grow, showing filamentation or lysis before division. Cells that were able to grow and form microcolonies showed highly diverse growth dynamics. The quality of the videos allowed for counting the cells over time and estimating the kinetic parameters lag time (λ) and maximum specific growth rate (μmax) for each microcolony originating from a single cell. To interpret the observations, the variability of the kinetic parameters was characterized using appropriate probability distributions and introduced to a stochastic model that allows for taking into account heterogeneity using Monte Carlo simulation. The model provides stochastic growth curves demonstrating that growth of single cells or small microbial populations is a pool of events each one of which has its own probability to occur. Simulations of the model illustrated how the apparent variability in population growth gradually decreases with increasing initial population size (N0). For bacterial populations withN0of >100 cells, the variability is almost eliminated and the system seems to behave deterministically, even though the underlying law is stochastic. We also used the model to demonstrate the effect of the presence and extent of a nongrowing population fraction on the stochastic growth of bacterial populations.

scholarly journals Amdinocillin (Mecillinam) Resistance Mutations in Clinical Isolates and Laboratory-Selected Mutants of Escherichia coli

2015 ◽  
Vol 59 (3) ◽  
pp. 1718-1727 ◽  
Author(s):  
Elisabeth Thulin ◽  
Martin Sundqvist ◽  
Dan I. Andersson
Keyword(s):  
Escherichia Coli ◽  
Clinical Isolates ◽  
Cysteine Biosynthesis ◽  
Resistance Mutations ◽  
Content Type ◽  
E Coli ◽  
Major Mechanism ◽  
Laboratory Selection ◽  
Lactam Antibiotic ◽  
Tract Infections

ABSTRACTAmdinocillin (mecillinam) is a β-lactam antibiotic that is used mainly for the treatment of uncomplicated urinary tract infections. The objectives of this study were to identify mutations that confer amdinocillin resistance on laboratory-isolated mutants and clinical isolates ofEscherichia coliand to determine why amdinocillin resistance remains rare clinically even though resistance is easily selected in the laboratory. Under laboratory selection, frequencies of mutation to amdinocillin resistance varied from 8 × 10−8to 2 × 10−5per cell, depending on the concentration of amdinocillin used during selection. Several genes have been demonstrated to give amdinocillin resistance, but here eight novel genes previously unknown to be involved in amdinocillin resistance were identified. These genes encode functions involved in the respiratory chain, the ribosome, cysteine biosynthesis, tRNA synthesis, and pyrophosphate metabolism. The clinical isolates exhibited significantly greater fitness than the laboratory-isolated mutants and a different mutation spectrum. ThecysBgene was mutated (inactivated) in all of the clinical isolates, in contrast to the laboratory-isolated mutants, where mainly other types of more costly mutations were found. Our results suggest that the frequency of mutation to amdinocillin resistance is high because of the large mutational target (at least 38 genes). However, the majority of these resistant mutants have a low growth rate, reducing the probability that they are stably maintained in the bladder. Inactivation of thecysBgene and a resulting loss of cysteine biosynthesis are the major mechanism of amdinocillin resistance in clinical isolates ofE. coli.

scholarly journals The fitness costs of antibiotic resistance mutations

2014 ◽  
Vol 8 (3) ◽  
pp. 273-283 ◽  
Author(s):  
Anita H. Melnyk ◽  
Alex Wong ◽  
Rees Kassen
Keyword(s):  
Antibiotic Resistance ◽  
Resistance Mutations ◽  
Fitness Costs ◽  
Antibiotic Resistance Mutations
Sign in / Sign up

Export Citation Format

Share Document