scholarly journals Mycobacteriophages to Treat Tuberculosis: Dream or Delusion?

Respiration ◽  
2021 ◽  
pp. 1-15
Author(s):  
Andreas H. Diacon ◽  
Carlos A. Guerrero-Bustamante ◽  
Bernd Rosenkranz ◽  
Francisco J. Rubio Pomar ◽  
Naadira Vanker ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Synergistic Effects ◽  
Case Reports ◽  
Resistant Bacteria ◽  
Human Consumption ◽  
Biological Entity ◽  
Optimal Dosage ◽  
Drug Resistant ◽  
Increased Risk ◽  
Phage Treatment

Rates of antimicrobial resistance are increasing globally while the pipeline of new antibiotics is drying up, putting patients with disease caused by drug-resistant bacteria at increased risk of complications and death. The growing costs for diagnosis and management of drug resistance threaten tuberculosis control where the disease is endemic and resources limited. Bacteriophages are viruses that attack bacteria. Phage preparations served as anti-infective agents long before antibiotics were discovered. Though small in size, phages are the most abundant and diverse biological entity on earth. Phages have co-evolved with their hosts and possess all the tools needed to infect and kill bacteria, independent of drug resistance. Modern biotechnology has improved our understanding of the biology of phages and their possible uses. Phage preparations are available to treat meat, fruit, vegetables, and dairy products against parasites or to prevent contamination with human pathogens, such as <i>Listeria monocytogenes, Escherichia coli</i>, or <i>Staphylococcus aureus</i>. Such phage-treated products are considered fit for human consumption. A number of recent case reports describe in great detail the successful treatment of highly drug-resistant infections with individualized phage preparations. Formal clinical trials with standardized products are slowly emerging. With its highly conserved genome and relative paucity of natural phage defence mechanisms <i>Mycobacterium tuberculosis</i> appears to be a suitable target for phage treatment. A phage cocktail with diverse and strictly lytic phages that kill all lineages of <i>M. tuberculosis,</i> and can be propagated on <i>Mycobacterium smegmatis</i>, has been assembled and is available for the evaluation of optimal dosage and suitable routes of administration for tuberculosis in humans. Phage treatment can be expected to be safe and active on extracellular organisms, but phage penetration to intracellular and granulomatous environments as well as synergistic effects with antibiotics are important questions to address during further evaluation.

scholarly journals Intravenous Honokiol in Drug-Resistant Cancer: Two Case Reports

2020 ◽  
Vol 19 ◽  
pp. 153473542092261
Author(s):  
Isaac Eliaz ◽  
Elaine Weil
Keyword(s):  
Drug Resistance ◽  
Cancer Patients ◽  
Complete Blood Count ◽  
Case Reports ◽  
Clinical Results ◽  
Drug Resistant ◽  
Magnolia Officinalis

Context: Long-term patient survival in cancer is affected by drug resistance. Honokiol (HNK) is a small-molecule polyphenol isolated from the bark and seed cones of Magnolia officinalis. HNK has been shown to enhance the effects of chemotherapy and inhibit drug resistance in preclinical models. HNK was well tolerated in multiple animal models when administered orally, intravenously (IV), and via intraperitoneal route. However, there are limited human data on the use of HNK in general, and specifically via IV (HNK-IV) in cancer. Objective: We aim to assess the efficacy, safety, and tolerability of HNK-IV in patients with drug-resistant tumors. Methods: This is a case study of 2 cancer patients who utilized HNK-IV as part of their cancer treatment regimen. The initial infusion of HNK was 10 mg/kg body weight, and subsequent treatments were increased up to 50 mg/kg according to individual tolerance, over 2 weeks. Results: Positive clinical response was achieved in both patients, including improved symptoms and quality of life. No serious adverse side effects occurred, and there were no adverse effects on laboratory parameters (complete blood count, kidney, and liver function). Transient sedation and minor nausea were noted and resolved postinfusion. Conclusions: This is the first report of HNK-IV in human patients. Given the positive clinical results, safety, and tolerability, the use of HNK-IV warrants further investigation regarding optimum formulation, and its use as adjunctive therapy in cancer patients.

scholarly journals Relationship between Ceftolozane-Tazobactam Exposure and Drug Resistance Amplification in a Hollow-Fiber Infection Model

2013 ◽  
Vol 57 (9) ◽  
pp. 4134-4138 ◽  
Author(s):  
Brian VanScoy ◽  
Rodrigo E. Mendes ◽  
Mariana Castanheira ◽  
Jennifer McCauley ◽  
Sujata M. Bhavnani ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Hollow Fiber ◽  
Drug Exposure ◽  
Resistant Bacteria ◽  
Infection Model ◽  
Drug Resistant ◽  
Dose Ratio ◽  
Bacterial Drug Resistance ◽  
Dosing Regimens ◽  
Selection Of

ABSTRACTIn an era of rapidly emerging antimicrobial-resistant bacteria, it is critical to understand the importance of the relationships among drug exposure, duration of therapy, and selection of drug resistance. Herein we describe the results of studies designed to determine the ceftolozane-tazobactam exposure necessary to prevent the amplification of drug-resistant bacterial subpopulations in a hollow-fiber infection model. The challenge isolate was a CTX-M-15-producingEscherichia coliisolate genetically engineered to transcribe a moderate level ofblaCTX-M-15. This organism'sblaCTX-M-15transcription level was confirmed by relative quantitative reverse transcription-PCR (qRT-PCR), β-lactamase hydrolytic assays, and a ceftolozane MIC value of 16 mg/liter. In these studies, the experimental duration (10 days), ceftolozane-tazobactam dose ratio (2:1), and dosing interval (every 8 h) were selected to approximate those expected to be used clinically. The ceftolozane-tazobactam doses studied ranged from 125-62.5 to 1,500-750 mg. Negative- and positive-control arms included no treatment and piperacillin-tazobactam at 4.5 g every 6 h, respectively. An inverted-U-shaped function best described the relationship between bacterial drug resistance amplification and drug exposure. The least- and most-intensive ceftolozane-tazobactam dosing regimens, i.e., 125-62.5, 750-375, 1,000-500, and 1,500-750 mg, did not amplify drug resistance, while drug resistance amplification was observed with intermediate-intensity dosing regimens (250-125 and 500-250 mg). For the intermediate-intensity ceftolozane-tazobactam dosing regimens, the drug-resistant subpopulation became the dominant population by days 4 to 6. The more-intensive ceftolozane-tazobactam dosing regimens (750-375, 1,000-500, and 1,500-750 mg) not only prevented drug resistance amplification but also virtually sterilized the model system. These data support the selection of ceftolozane-tazobactam dosing regimens that minimize the potential for on-therapy drug resistance amplification.

scholarly journals Analysis of Drug Resistance in Helicobacter Pylori by Complete Genome Sequencing in Bama County, Guangxi, China

2020 ◽  
Author(s):  
yanqiang huang ◽  
Xiao-Hua Li ◽  
Yong-Yi Huang ◽  
Xian-ke Luo ◽  
Yan-Chun Qin ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Genome Sequencing ◽  
Complete Genome ◽  
Gene Knockout ◽  
Resistance Rate ◽  
Resistant Bacteria ◽  
Drug Resistant ◽  
Minimal Inhibitory Concentrations ◽  
Complete Genome Sequencing ◽  
Clarithromycin Resistance

Abstract Background: The resistance rate of clinical Helicobacter pylori (Hp) isolates has increased, however, the mechanism of drug resistance is unclear. In this study, we isolated drug-resistant Hp strains isolated from different areas and different populations of China for genomic analysis.Objectives: The aim of this study was to investigate drug resistance in Hp from Bama County, Guangxi, China.Methods: Minimal inhibitory concentrations (MICs) of clarithromycin, metronidazole and levofloxacin were determined and complete genome sequencing was performed with annotation. The presence of hp1181 and hp1184 genes was detected by RT-PCR. The relationships between hp1181, hp1184 and clarithromycin resistance were confirmed by gene mutation and drug-resistant strains. Results: Three drug-resistant Hp strains were isolated from patients with gastritis in Bama County. The strains showed a high degree of homology with hp26695 through complete genome detection and identification. Differences in genome sequences, gene quantity and gene characteristics were detected amongst the three strains. Prediction and analysis of the function on drug-resistant genes indicated that the RNA expression of hp1181 and hp1184 increased in the three strains that were the same in the artificially induced clarithromycin-resistant bacteria. After gene knockout, the drug sensitivity of the strains increased significantly.Conclusions: The expressions of the genes hp1184 and hp1181 were associated with clarithromycin resistance in the Hp from Bama, Guangxi.

scholarly journals Two Lytic Bacteriophages That Depend on theEscherichia coliMulti-Drug Efflux GenetolCand Differentially Affect Bacterial Growth and Selection

2018 ◽  
Author(s):  
Alita R. Burmeister ◽  
Rose G. Bender ◽  
Abigail Fortier ◽  
Adam J. Lessing ◽  
Benjamin K. Chan ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Antibiotic Resistance ◽  
Resistance Gene ◽  
Bacterial Growth ◽  
Bacterial Pathogens ◽  
Antibiotic Resistance Gene ◽  
Resistant Bacteria ◽  
Drug Efflux ◽  
Drug Resistant ◽  
Resistant Mutants

AbstractBacterial pathogens are increasingly evolving drug resistance under natural selection from antibiotics in medicine, agriculture, and nature. Meanwhile, bacteria ubiquitously encounter bacteriophages and can rapidly evolve phage resistance. However, the role of phages in interacting with drug-resistant and drug-sensitive bacteria remains unclear. To gain insight into such relationships, we screened for and characterized phages that rely on the multi-drug efflux pump genetolC. First, we screened a collection of 33 environmental and commercialEscherichia coliphages for their ability to infect cells that lackedtolC. Our screen revealed two phages that had reduced efficiency of plating (EOP) on thetolCknockout compared to wild type. We further characterized these phages with bacterial growth curves, transmission electron microscopy, and analysis of phage-resistant mutants. Phage U136B is a curly-tailed virus in familySiphoviridaewith no ability to infect atolCknockout, suggesting TolC is the U136B receptor. Phage 132 is a contractile-tailed virus in familyMyoviridaewith reduced EOP on cells lackingompFand its positive regulatorstolCandompR. U136B and 132 differentially effect bacterial growth and lysis, and U136B-resistant mutants contain mutations of thetolCgene. Together, these results show that thetolCgene involved in drug resistance can modify bacteria-phage interactions in multiple ways, altering bacterial lysis and selection. These new phages offer utility for studying evolution, tradeoffs, and infection mechanisms.ImportanceBacteria face strong selection by antibiotics in medicine and agriculture, resulting in increasing levels of drug resistance among bacterial pathogens. Slowing this process will require an understanding of the environmental contexts in which drug resistance evolutionarily increases or decreases. In this study, we investigate two newly-isolated bacteriophages that rely on a bacterial antibiotic resistance gene. These bacteriophages vary in their interactions with drug-resistant bacteria, with one of the phages selecting for phage-resistant mutants that have mutations in the antibiotic resistance gene. Further study of these new phages will be useful to understanding evolutionary tradeoffs and how phages might be applied in natural settings to reverse the problem of drug resistance.

scholarly journals Analysis of drug resistance in Helicobacter pylori by complete genome sequencing in Bama County, Guangxi, China

2020 ◽  
Author(s):  
yanqiang huang ◽  
Xiao-Hua Li ◽  
Yong-Yi Huang ◽  
Xian-ke Luo ◽  
Li-juan Zhao ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Helicobacter Pylori ◽  
Genome Sequencing ◽  
Complete Genome ◽  
Gene Knockout ◽  
Resistance Rate ◽  
Resistant Bacteria ◽  
Drug Resistant ◽  
Complete Genome Sequencing ◽  
Clarithromycin Resistance

Abstract The resistance rate of clinical Helicobacter pylori (Hp) isolates has increased, however, the mechanism of drug resistance is unclear. In this study, we isolated drug-resistant Hp strains isolated from different areas and different populations of China for genomic analysis. The aim of this study was to investigate drug resistance in Hp from Bama County, Guangxi, China. Minimal inhibitory concentrations (MICs) of clarithromycin, metronidazole and levofloxacin were determined and complete genome sequencing was performed with annotation. The presence of hp1181 and hp1184 genes was detected by RT-PCR. The relationships between hp1181, hp1184 and clarithromycin resistance were confirmed by gene mutation and drug-resistant strains. Three drug-resistant Hp strains were isolated from patients with gastritis in Bama County. The strains showed a high degree of homology with hp26695 through complete genome detection and identification. Differences in genome sequences, gene quantity and gene characteristics were detected amongst the three strains. Prediction and analysis of the function on drug-resistant genes indicated that the RNA expression of hp1181 and hp1184 increased in the three strains that were the same in the artificially induced clarithromycin-resistant bacteria. After gene knockout, the drug sensitivity of the strains increased significantly. In summary, The expressions of the genes hp1184 and hp1181 were associated with clarithromycin resistance in the Hp from Bama, Guangxi.

scholarly journals Detection of Drug Susceptible and Resistant Viridans Streptococci spp., Staphylococcus Aureus, Klebsiella Pneumoniae and E.coli in Complete Denture Patients and Visualisation using Scanning Electron Microscopy

2020 ◽  
Author(s):  
Leoney Andonissamy ◽  
Suma Karthigeyan ◽  
Seyed Asharaf Ali
Keyword(s):  
Staphylococcus Aureus ◽  
Drug Resistance ◽  
Klebsiella Pneumoniae ◽  
Oral Cavity ◽  
Antibiotic Sensitivity ◽  
Complete Denture ◽  
Resistant Bacteria ◽  
Drug Resistant ◽  
Drug Resistant Bacteria ◽  
Sensitivity Tests

Introduction: The bacteria colonising the oral cavity and the dentures acquire drug resistance due to frequent usage of antibiotics systemically and application of mouth rinses and denture disinfectants locally. These multidrug resistant bacteria pose potential threat to the health of the patient as infections caused by them do not respond to conventional antibiotics. Aim: The present study aims at detecting the drug resistant bacteria in patients who wear complete dentures. Materials and Methods: The study is a descriptive study and follows laboratory invitro study design involving 30 complete denture patients. Swabs were collected from their oral cavity as well as complete denture surfaces. Antibiotic sensitivity tests were performed for the following bacteriae namely Viridans streptococci species, Staphylococcus aureus, Klebsiella pneumoniae and E.coli. Isolation of the bacteria were done by means of selective media and subjected to biochemical tests. The 16S rRNA sequencing was done to ascertain the microorganisms by which 20 isolates of each of the selective bacteria were obtained. The bacteria were classified as sensitive, intermediate sensitive and resistant based on antibiotic sensitivity tests. Those isolates which exhibited Multi-Drug Resistance (MDR) were visualised using SEM. Results:Viridans streptococci spp. (40%) and Staphylococcus aureus (25%) isolates were resistant to Amoxiclavulinic acid and Methicilin, whereas Klebsiella pneumoniae (30%) and (30%) E.coli isolates were most resistant to Cefotaxime and Doxicilin. Conclusion: Drug resistant bacteria have been identified from complete dentures and oral cavity in the present study. Antibiotic sensitivity tests, 16S rRNA sequencing and SEM are vital investigative tools to detect and to visualise drug resistant bacteria. Cell density, Extracellular Polymeric Substances (EPS) and capsule could be important factors for providing drug resistance.

scholarly journals Isolation and Identification of Multi-drug Resistant Bacteria from various sources and Antimicrobial Activity of Terminalia chebula Retz against isolated Multi-drug Resistant Bacteria

2021 ◽  
Vol 11 (4) ◽  
pp. 7338-7344
Author(s):  
Tamalika Chakraborty ◽  
Kanchan Chettri ◽  
Sumana Chatterjee ◽  
Lopamudra Datta ◽  
Abhijit Sengupta
Keyword(s):  
Drug Resistance ◽  
Minimum Inhibitory Concentration ◽  
Inhibitory Concentration ◽  
Minimum Bactericidal Concentration ◽  
Bacterial Activity ◽  
Resistant Bacteria ◽  
Drug Resistant ◽  
Terminalia Chebula ◽  
Isolation And Identification ◽  
Drug Resistant Bacteria

Drug resistance is a threat to civilization, which results from over-prescription and irrational use of antibiotics. This has led to an increased demand for novel leads of herbal origin to overcome drug resistance. The present work involves the screening of various antibiotics against isolated Staphylococcus sp. from Hospital Effluent and the Minimum Inhibitory concentration for antibiotics namely Vancomycin, Erythromycin and Oxacillin were found to be 7.33+0.6 µg/ml 25.33+0.6 µg/ml and 27.33+0.6 µg/ml respectively whereas Minimum bactericidal concentration of Vancomycin, Erythromycin and oxacillin was found to be 180µg/ml; 146.67 + 0.3 µg/ml and 96.66 + 0.6 µg/ml respectively. Thus, the isolated bacteria were proved to be Multi-Drug Resistant. Haritaki (Terminalia chebula Retz) is given potential importance in Ayurveda for its properties to cure and prevent diseases. Terminalia chebula Retz is often known as “King of Medicines” and enlisted in Ayurveda for its extraordinary therapeutic contribution. The proved Multi-Drug Resistant bacteria was further subjected to a crude extract of Haritaki. Minimum Inhibitory Concentration for Terminalia chebula was found to be 1.33 +0.3 mg/ml and thus proved to be exhibiting potential anti-bacterial activity against isolated Multi-Drug Resistant Staphylococcus sp.

scholarly journals Drug Resistance of Ocular Bacteria Considering Biofilm Mechanism

2021 ◽  
Vol 271 ◽  
pp. 03041
Author(s):  
Yutong Liu ◽  
Xuanrong Xu
Keyword(s):  
Experimental Study ◽  
Drug Resistance ◽  
Bacterial Biofilm ◽  
Resistant Bacteria ◽  
Drug Resistant ◽  
Conjugation System ◽  
Resistant Genes ◽  
Drug Resistant Bacteria ◽  
Bacterial Drug Resistance ◽  
The Relationship

In order to further analyze the relationship between the coating mechanism of microorganisms and their drug resistance, a study of ocular bacterial drug resistance considering the coating mechanism of microorganisms was proposed. Firstly, the mechanism of drug resistance was analyzed, and on this basis, the experimental study was carried out. Staphylococcus aureus DH5 with RP4 was used as the control α( R) Objective to investigate the relationship between drug-resistant bacteria and coating mechanism in the cross genus conjugation system of Pseudomonas aeruginosa PAOi and donor bacteria. The conclusion is that: under the condition that the horizontal transfer of drug-resistant genes between transgeneric bacteria in biofilm is inhibited, the frequency of drug-resistant gene conjugation and transfer gradually decreases, and the inhibition of the formation of drug-resistant bacterial biofilm will directly lead to the decrease of bacterial drug resistance.

Roles of Raf/MEK/ERK and PI3K/Akt/mTOR Signaling and p53 Pathways on Apoptosis, Drug Resistance and Therapeutic Sensitivity of Early Hematopoietic Precursor Cells

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 503-503
Author(s):  
Stephen Lee Abrams ◽  
Linda S Steelman ◽  
Melissa L Skolosky ◽  
Giovanni Ligresti ◽  
Massimo Libra ◽  
...  
Keyword(s):  
Stem Cells ◽  
Drug Resistance ◽  
Synergistic Effects ◽  
Flow Cytometric Analysis ◽  
Dominant Negative ◽  
Drug Resistant ◽  
Hematopoietic Stem ◽  
Doxorubicin Treatment ◽  
Hematopoietic Precursor ◽  
Resistant Cells

Abstract The interleukin-3 (IL-3) dependent FL5.12 hematopoietic precursor cell line was isolated from murine fetal liver, an important site of early hematopoiesis, by panning with an anti-AA4 antibody and culturing the cells in medium containing IL-3. The AA4 cell antigen (human analogue, Clq Receptor) is a key cell surface marker expressed on early hematopoietic stem cells along with the IL-3R (CD123) and others. Upon Hoechst-33342 staining and flow cytometric analysis, FL5.12 cells normally have approximately 0.4% of the cells present in side population (SP) which are proposed to possess “stem cell like characteristics”. Some leukemic stem cells often display drug resistance properties. FL5.12 cells are normally sensitive to chemotherapeutic drugs such as doxorubicin, however, drug resistant cells (FL/Doxo) were isolated by subcloning the cells in doxorubicin. These drug resistant cells contain approximately 2-fold more SP cells than drug sensitive FL5.12 cells. Drug resistance was associated with 6-fold increased ERK activation and 11-fold decreased p53 induction after doxorubicin treatment. Furthermore the drug resistant cells displayed decreased apoptosis (1.8 fold) and caspase 3, 8 and 10 activation (4.2, 2.3, 2 fold respectively) upon culture with doxorubicin than the parental cells. A 3-fold higher level of proteasomal degradation of p53 was observed in the drug resistant cells which was due to 8-fold higher levels of MDM2. Drug resistant FL/Doxo cells were more sensitive to proteosome inhibitors (IC50 of 75 nM compared to 125 nM for parental cells). Treatment with proteosome inhibitors resulted in 12-fold and 2-fold more p53 detection in FL/Doxo and FL5.12 cells respectively. Synergistic responses to doxorubicin and proteosome inhibitor treatment were observed as the IC50 for doxorubicin was reduced 16- and 5-fold respectively with FL/Doxo and FL5.12 respectively. FL/Doxo cells were also highly sensitive to mTOR inhibitors and synergistic effects were observed upon combining doxorubicin and rapamycin as the IC50s decreased 40- and 6-fold for FL/Doxo and FL5.12 cells respectively, documenting the importance of the mTOR pathway in their drug resistance. Introduction of dominant negative (DN) p53 or activated MEK1 (MEK1 CA) further increased the resistance of the FL/Doxo cells to doxorubicin approximately 18- and 34-fold respectively. The DN p53 or MEK1 CA transduced cells contained 3.3- and 5.4-fold more SP positive cells than parental FL5.12 cells respectively. While both DN p53 and MEK1 CA increased drug resistance and the frequency of SP cells, this occurred by different mechanisms. DN p53 suppressed Bax induction after doxorubicin treatment and decreased the sensitivity of the cells to proteosome (1.6-fold), MEK (1.2-fold), MDM- 2 (5-fold) and mTOR (3-fold) inhibitors compared to the parental FL5.12 cells. MEK1 CA also decreased the sensitivity to proteosome inhibitors 3-fold, yet the cells remained sensitive to MEK, mTOR and MDM2 inhibitors. Thus while DN p53 or MEK1 CA both increased the frequency of SP hematopoietic “leukemia stem” like cells, they do this by different mechanisms which also alters the sensitivities of small molecule inhibitors. Mutation of p53 or activation of the Raf/MEK/ERK pathway in leukemia stem cells may render them resistant to chemotherapy as well as certain targeted therapeutic approaches.

scholarly journals Adaptation Through Lifestyle Switching Sculpts the Fitness Landscape of Evolving Populations: Implications for the Selection of Drug-Resistant Bacteria at Low Drug Pressures

Genetics ◽  
2019 ◽  
Vol 211 (3) ◽  
pp. 1029-1044 ◽  
Author(s):  
Nishad Matange ◽  
Sushmitha Hegde ◽  
Swapnil Bodkhe
Keyword(s):  
Drug Resistance ◽  
Drug Exposure ◽  
Fitness Landscape ◽  
Rifampicin Resistance ◽  
Resistant Bacteria ◽  
Type I ◽  
Drug Resistant ◽  
The Impact ◽  
Selection Of ◽  
Evolving Populations

Novel genotypes evolve under selection through mutations in pre-existing genes. However, mutations have pleiotropic phenotypic effects that influence the fitness of emerging genotypes in complex ways. The evolution of antimicrobial resistance is mediated by selection of mutations in genes coding for antibiotic-target proteins. Drug-resistance is commonly associated with a fitness cost due to the impact of resistance-conferring mutations on protein function and/or stability. These costs are expected to prohibit the selection of drug-resistant mutations at low drug pressures. Using laboratory evolution of rifampicin resistance in Escherichia coli, we show that when exposed intermittently to low concentration (0.1 × minimal inhibitory concentration) of rifampicin, the evolution of canonical drug resistance was indeed unfavorable. Instead, these bacterial populations adapted by evolving into small-colony variants that displayed enhanced pellicle-forming ability. This shift in lifestyle from planktonic to pellicle-like was necessary for enhanced fitness at low drug pressures, and was mediated by the genetic activation of the fim operon promoter, which allowed expression of type I fimbriae. Upon continued low drug exposure, these bacteria evolved exclusively into high-level drug-resistant strains through mutations at a limited set of loci within the rifampicin-resistance determining region of the rpoB gene. We show that our results are explained by mutation-specific epistasis, resulting in differential impact of lifestyle switching on the competitive fitness of different rpoB mutations. Thus, lifestyle-alterations that are selected at low selection pressures have the potential to modify the fitness effects of mutations, change the genetic structure, and affect the ultimate fate of evolving populations.

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