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 Multidrug Resistance (MDR) and Collateral Sensitivity in Bacteria, with Special Attention to Genetic and Evolutionary Aspects and to the Perspectives of Antimicrobial Peptides—A Review

Pathogens ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 522
Author(s):  
András Fodor ◽  
Birhan Addisie Abate ◽  
Péter Deák ◽  
László Fodor ◽  
Ervin Gyenge ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Multidrug Resistance ◽  
Antimicrobial Peptides ◽  
Resistance Genes ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Mobility Patterns ◽  
Collateral Sensitivity ◽  
Resistance Evolution ◽  
Antimicrobial Peptide Resistance

Antibiotic poly-resistance (multidrug-, extreme-, and pan-drug resistance) is controlled by adaptive evolution. Darwinian and Lamarckian interpretations of resistance evolution are discussed. Arguments for, and against, pessimistic forecasts on a fatal “post-antibiotic era” are evaluated. In commensal niches, the appearance of a new antibiotic resistance often reduces fitness, but compensatory mutations may counteract this tendency. The appearance of new antibiotic resistance is frequently accompanied by a collateral sensitivity to other resistances. Organisms with an expanding open pan-genome, such as Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae, can withstand an increased number of resistances by exploiting their evolutionary plasticity and disseminating clonally or poly-clonally. Multidrug-resistant pathogen clones can become predominant under antibiotic stress conditions but, under the influence of negative frequency-dependent selection, are prevented from rising to dominance in a population in a commensal niche. Antimicrobial peptides have a great potential to combat multidrug resistance, since antibiotic-resistant bacteria have shown a high frequency of collateral sensitivity to antimicrobial peptides. In addition, the mobility patterns of antibiotic resistance, and antimicrobial peptide resistance, genes are completely different. The integron trade in commensal niches is fortunately limited by the species-specificity of resistance genes. Hence, we theorize that the suggested post-antibiotic era has not yet come, and indeed might never come.

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 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 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 609. Differing Genotypic Contexts Between E. coli and A. baumannii Modulate the Role of blaADC-7 in the Development of Antibiotic Collateral Sensitivity

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S284-S285
Author(s):  
Erin McClure ◽  
Julia Newman ◽  
Nikhil Krishnan ◽  
Joseph Rutter ◽  
Andrea M Hujer ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Fold Increase ◽  
Protein Product ◽  
Coli Strain ◽  
Fourth Generation ◽  
Clinical Strain ◽  
Health Crisis ◽  
E Coli ◽  
Collateral Sensitivity ◽  
Resistance Evolution

Abstract Background Antibiotic resistance is a global health crisis. While persistent drug discovery of novel antibiotics has previously been relied upon to thwart resistance, evolution inevitably perseveres. While genes conferring antibiotic resistance have previously been characterized, it is unclear how varying genetic contexts can change the antibiotic resistance phenotype a given gene confers. Methods The DH10B strain of E. coli was transformed with a blaADC-7 plasmid. In 12 evolutionary replicates, the modified E. coli strain and a clinical strain of A. baumannii containing the same resistance gene were passaged daily for 10 days on cefepime gradient agar plates with gradually increasing concentrations of cefepime. MICs of cefepime and a diverse set of 15 other drugs were determined for the parental strains and after the final passage passage. MIC of cefepime after intermediary passages were determined for select replicates. Lastly the blaADC-7 gene after the final passage was sequenced. Results At the end of 10 passages, collateral sensitivity in A. baumannii was observed to tigecycline and fosfomycin in 5 and 6 replicates respectively, out of 12 total. 4 out of 12 E. coli replicates displayed collateral sensitivity to minocycline (Figure 1). In the third E. coli replicate, Sanger sequencing revealed a novel S286R mutation in blaADC-7 appearing in passage seven which preceded a several log fold increase in the MIC of cefepime (Figures 2 and 3). No additional mutations were found in the other evolutionary replicates. Conclusion Patterns of resistance varied among antibiotics of the same class, (e.g., tetracyclines, fourth-generation cephalosporins) in both E. coli and A. baumannii; however, A. baumannii expressed less widespread collateral resistance than E. coli. A previously undiscovered S286R mutation in blaADC-7 coincided with a pronounced increased in resistance to cefepime. Further studies are required to determine whether this mutation gives rise to a structural change in the protein product. Given that no other mutations were found, resistance to cefepime and subsequent collateral resistance to other antibiotics may have developed due to epigenetic changes or mutations outside the blaADC-7 genes. Indeed, future experiments with whole-genome sequencing may reveal such changes. Disclosures All authors: No reported disclosures.

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.

scholarly journals Determining the Rate of Development of Antibiotic Resistance to Streptomycin and Doxycycline in Escherichia coli

2019 ◽  
pp. 2-7
Author(s):  
Dominique Tertigas ◽  
Gemma Barber
Keyword(s):  
Escherichia Coli ◽  
Antibiotic Resistance ◽  
Combination Treatment ◽  
Bacterial Resistance ◽  
Cross Resistance ◽  
Resistant Bacteria ◽  
Small Scale ◽  
Rate Of Development ◽  
E Coli ◽  
Successive Generations

Antibiotic resistance is a pressing issue in the medical field today. It is important to understand the development of bacterial resistance to implement effective preventative measures against antibiotic resistant bacteria. This study investigated the rate at which Escherichia coli (E. coli), a common pathogen, developed resistance to streptomycin and doxycycline, as Oz et al. (2014) showed differing levels of resistance in E. coli to these two antibiotics. The development of antibiotic resistance was measured by adding E. coli to 96-well plates in the presence of increasing doses of doxycycline, streptomycin, or a combination treatment. Successive generations were added to the same treatments to see whether they would grow at higher concentrations of antibiotic. The change in minimum inhibitory concentration for streptomycin and doxycycline was determined as the bacteria became increasingly resistant to each antibiotic. The fastest rate of antibiotic resistance was observed for streptomycin, with doxycycline resistance exhibiting a slower rate of development. The rate of resistance development for the combination treatment was the slowest, potentially due to small differences in target domains. Some cross-resistance was also observed. This study provides a small-scale methodological basis and preliminary insight on antibiotic resistance trends for two antibiotic classes and a combination treatment.

scholarly journals Evolution of Honey Resistance in Experimental Populations of Bacteria Depends on the Type of Honey, and Has no Major Side Effects for Antibiotic Susceptibility

2020 ◽  
Author(s):  
Anna M. Bischofberger ◽  
Katia R. Pfrunder Cardozo ◽  
Michael Baumgartner ◽  
Alex R. Hall
Keyword(s):  
Antibiotic Resistance ◽  
Wound Care ◽  
Single Gene ◽  
Fold Increase ◽  
Medical Application ◽  
Single Step ◽  
Cross Resistance ◽  
Serial Transfer ◽  
Collateral Sensitivity ◽  
Collateral Effects

AbstractWith rising antibiotic resistance, alternative treatments for communicable diseases are increasingly relevant. One possible alternative for some types of infections is honey, used in wound care since before 2000 BCE and more recently in licensed, medical-grade products. However, it is unclear whether medical application of honey results in the evolution of bacterial honey resistance, and whether this has collateral effects on other bacterial traits such as antibiotic resistance. Here, we used single-step screening assays and serial transfer at increasing concentrations to isolate honey-resistant mutants of Escherichia coli. We only detected bacteria with consistently increased resistance to the honey they evolved in with two of the four tested honey products, and the observed increases were small (maximum two-fold increase in IC90). Genomic sequencing and experiments with single-gene knockouts showed a key mechanism by which bacteria increased their honey resistance was by mutating genes involved in detoxifying methylglyoxal, which contributes to the antibacterial activity of Leptospermum honeys. Crucially, we found no evidence that honey adaptation conferred cross-resistance or collateral sensitivity against nine antibiotics from six different classes. These results reveal constraints on bacterial adaptation to different types of honey, improving our ability to predict downstream consequences of wider honey application in medicine.

scholarly journals Mycoplasma genitalium in Singapore is Associated with Chlamydia trachomatis Infection and Displays High Macrolide and Fluoroquinolone Resistance Rates

2020 ◽  
Author(s):  
Tim Hart ◽  
Wen Ying Tang ◽  
Siti Aminah Mansoor ◽  
Martin Tze-Wei Chio ◽  
Timothy Sebastian Barkham
Keyword(s):  
Antibiotic Resistance ◽  
Sexual Health ◽  
Mycoplasma Genitalium ◽  
Routine Screening ◽  
High Rate ◽  
Fluoroquinolone Resistance ◽  
Health Clinic ◽  
Resistance Mutations ◽  
Transmitted Infection ◽  
Sexually Transmitted

Abstract Background: Mycoplasma genitalium is an emerging sexually transmitted infection, with increasing rates of resistance to fluroquinolones and macrolides, the recommended treatments. Despite this, M. genitalium is not part of routine screening for Sexually Transmitted Infections (STIs) in many countries and the prevalence of infection and patterns of disease remain to be determined in many populations. Such data is of particular importance in light of the reported rise in antibiotic resistance in M. genitalium isolates. Methods : Urine and urethral swab samples were collected from the primary public sexual health clinic in Singapore and tested for C. trachomatis (CT) or N. gonorrhoeae (NG) infection and for the presence of M. genitalium . Antibiotic resistance in M. genitalium strains detected was determined by screening for genomic mutations associated with macrolide and fluroquinolone resistance. Results : We report the results of a study into M. genitalium prevalence at the national sexual health clinic in Singapore. M. genitalium was heavily associated with CT infection (8.1% of cases), but present in only of 2.4% in CT negative cases and not independently linked to NG infection. Furthermore, we found high rates of resistance mutations to both macrolides (25%) and fluoroquinolones (37.5%) with a majority of resistant strains being dual-resistant. Resistance mutations were only found in strains from patients with CT co-infection. Conclusions : Our results support targeted screening of CT positive patients for M. genitalium as a cost-effective strategy to reduce the incidence of M. genitalium in the absence of comprehensive routine screening. The high rate of dual resistance also highlights the need to ensure the availability of alternative antibiotics for the treatment of multi-drug resistant M. genitalium isolates.

scholarly journals Microevolution of Mycobacterium tuberculosis hetero-resistance subpopulations in a patient receiving 27 years of tuberculosis treatment in Germany

2021 ◽  
Author(s):  
Lindsay Sonnenkalb ◽  
Gerald Strohe ◽  
Viola Dreyer ◽  
Sönke Andres ◽  
Doris Hillemann ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Treatment Failure ◽  
Evolutionary Dynamics ◽  
Drug Susceptibility ◽  
Drug Resistant ◽  
Sequencing Data ◽  
Resistance Mutations ◽  
Treatment Regimens ◽  
Resistance Evolution ◽  
Potential Risk Factors

Pre-existing and newly emerging resistant pathogen subpopulations (hetero-resistance) are potential risk factors for treatment failure of multi/extensively drug resistant (MDR/XDR) tuberculosis (TB). Intra-patient evolutionary dynamics of Mycobacterium tuberculosis complex (Mtbc) strains and their implications on treatment outcomes are still not completely understood. Methods To elucidate how Mtbc strains escape therapy, we analysed 13 serial isolates by whole genome sequencing from a German patient. Sequencing data was compared to phenotypic drug susceptibility profiles, and the patient’s collective 27-year treatment history, to further elucidate factors fostering intra-patient resistance evolution. Results The patient endured five distinct TB episodes, ending in resistances to 16 drugs and a nearly untreatable XDR-TB infection. The first isolate obtained, during the patient’s 5th TB episode, presented fixed resistance mutations to seven anti-TB drugs including isoniazid, rifampicin, streptomycin, pyrazinamide, prothionamide, para-aminosalicyclic acid and cycloserin/terizidone. Over the next 13 years a dynamic evolution with co-existing, heterogeneous subpopulations was observed in six out of 13 sequential bacterial isolates. The emergence of drug-resistant subpopulations coincided with frequent changes in treatment regimens, which often included two or less active compounds. This evolutionary arms race between competing sub-populations, ultimately resulted in the fixation of a single XDR variant. Conclusion Our data demonstrates the complex intra-patient microevolution of Mtbc subpopulations during failing MDR/XDR-TB treatment. Designing effective treatment regimens based on rapid detection of (hetero-) resistance is key to avoid resistance development and treatment failure.

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