scholarly journals Phenotypic Heterogeneity Facilitates Survival While Hindering the Evolution of Drug Resistance

2021 ◽  
Author(s):  
Joshua Guthrie ◽  
Daniel A. Charlebois
Keyword(s):  
Drug Resistance ◽  
Drug Treatment ◽  
Genetic Resistance ◽  
Treatment Strategies ◽  
Genetic Mutation ◽  
Drug Resistant ◽  
Resistance Mutations ◽  
Antimicrobial Drugs ◽  
Antimicrobial Drug Resistance ◽  
Population Extinction

ABSTRACTRising rates of resistance to antimicrobial drugs threatens the effective treatment of infections across the globe. Recently, it has been shown that drug resistance can emerge from non-genetic mechanisms, such as fluctuations in gene expression, as well as from genetic mutations. However, it is unclear how non-genetic drug resistance affects the evolution of genetic drug resistance. We develop deterministic and stochastic population models to quantitatively investigate the transition from non-genetic to genetic resistance during the exposure to static and cidal drugs. We find that non-genetic resistance facilitates the survival of cell populations during drug treatment, but that it hinders the development of genetic resistance due to competition between the non-genetically and genetically resistant subpopulations. The presence of non-genetic drug resistance is found to increase the first-appearance, establishment, and fixation times of drug resistance mutations, while increasing the probability of mutation before population extinction during cidal drug treatment. These findings advance our fundamental understanding of the evolution of drug resistance and may guide novel treatment strategies for patients with drug-resistant infections.SIGNIFICANCEAntimicrobial (drug) resistance is predicted to kill as many as 10 million people per year and cost over 100 trillion USD in cumulative lost production globally by 2050. To mitigate these socio-economic costs, we need to fundamentally understand the drug resistance process. We investigate the effect that different forms of drug resistance have on the evolution of drug resistance using mathematical modeling and computer simulations. We find that the presence of non-genetically drug-resistant cells (whose resistance is temporary and not encoded in a genetic mutation) allows the population to survive drug treatment, while at the same time slowing down the evolution of permanent genetic drug resistance. These findings have important implications for advancing evolutionary theory and for developing effective “resistance-proof” treatments.

Antibiotic Resistance in the Veterinary Perspective

2019 ◽  
pp. 142-157
Author(s):  
Sophia Inbaraj ◽  
Vamshi Krishna Sriram ◽  
Prasad Thomas ◽  
Abhishek Verma ◽  
Pallab Chaudhuri
Keyword(s):  
Drug Resistance ◽  
Antibiotic Resistance ◽  
Food Chain ◽  
Bacterial Species ◽  
Animal Husbandry ◽  
Drug Resistant ◽  
Antimicrobial Drug Resistance ◽  
Antibiotic Drug ◽  
Antibiotics Use ◽  
Genetic Mechanisms

Antibiotic resistance is an emerging threat to achieving one health all over the globe. The phenomenon leads to the emergence of drug-resistant microbes previously susceptible to an antibiotic. Drug-resistant microbes are the major reasons for medical complications like patient mortality and treatment failure. Unregulated use of antibiotics in animal husbandry is one of the major reasons for the emergence of antibiotic resistance. The resistance enters the human population mainly through the food chain. The genetic markers associated with drug resistance spread among different bacterial species by horizontal gene transfer mechanisms. Therefore, regulation of antibiotics use in animal husbandry and proper safety measures at farm level are necessary to check drug-resistant microbes entering the food chain. This chapter discusses the antibiotics, antibiotic resistance, genetic mechanisms involved, the spread of resistance, and also the available strategies to combat antimicrobial drug resistance.

scholarly journals Low-Frequency Drug Resistance in HIV-Infected Ugandans on Antiretroviral Treatment Is Associated with Regimen Failure

2016 ◽  
Vol 60 (6) ◽  
pp. 3380-3397 ◽  
Author(s):  
Fred Kyeyune ◽  
Richard M. Gibson ◽  
Immaculate Nankya ◽  
Colin Venner ◽  
Samar Metha ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Treatment Failure ◽  
Sanger Sequencing ◽  
Antiretroviral Treatment ◽  
Low Frequency ◽  
Drug Resistant ◽  
Viral Quasispecies ◽  
Resistance Mutations ◽  
Drug Resistance Mutations ◽  
Hiv 1

Most patients failing antiretroviral treatment in Uganda continue to fail their treatment regimen even if a dominant drug-resistant HIV-1 genotype is not detected. In a recent retrospective study, we observed that approximately 30% of HIV-infected individuals in the Joint Clinical Research Centre (Kampala, Uganda) experienced virologic failure with a susceptible HIV-1 genotype based on standard Sanger sequencing. Selection of minority drug-resistant HIV-1 variants (not detectable by Sanger sequencing) under antiretroviral therapy pressure can lead to a shift in the viral quasispecies distribution, becoming dominant members of the virus population and eventually causing treatment failure. Here, we used a novel HIV-1 genotyping assay based on deep sequencing (DeepGen) to quantify low-level drug-resistant HIV-1 variants in 33 patients failing a first-line antiretroviral treatment regimen in the absence of drug-resistant mutations, as screened by standard population-based Sanger sequencing. Using this sensitive assay, we observed that 64% (21/33) of these individuals had low-frequency (or minority) drug-resistant variants in the intrapatient HIV-1 population, which correlated with treatment failure. Moreover, the presence of these minority HIV-1 variants was associated with higher intrapatient HIV-1 diversity, suggesting a dynamic selection or fading of drug-resistant HIV-1 variants from the viral quasispecies in the presence or absence of drug pressure, respectively. This study identified low-frequency HIV drug resistance mutations by deep sequencing in Ugandan patients failing antiretroviral treatment but lacking dominant drug resistance mutations as determined by Sanger sequencing methods. We showed that these low-abundance drug-resistant viruses could have significant consequences for clinical outcomes, especially if treatment is not modified based on a susceptible HIV-1 genotype by Sanger sequencing. Therefore, we propose to make clinical decisions using more sensitive methods to detect minority HIV-1 variants.

scholarly journals Impact of pretreatment low-abundance HIV-1 drug-resistant variants on virological failure among HIV-1/TB-co-infected individuals

2020 ◽  
Vol 75 (11) ◽  
pp. 3319-3326
Author(s):  
Benjamin Chimukangara ◽  
Jennifer Giandhari ◽  
Richard Lessells ◽  
Nonhlanhla Yende-Zuma ◽  
Benn Sartorius ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Virological Failure ◽  
Statistical Significance ◽  
Drug Resistant ◽  
Resistance Mutations ◽  
Next Generation Sequencing Ngs ◽  
Ngs Data ◽  
The Impact ◽  
Hiv 1 ◽  
Control Study

Abstract Objectives To determine the impact of pretreatment low-abundance HIV-1 drug-resistant variants (LA-DRVs) on virological failure (VF) among HIV-1/TB-co-infected individuals treated with NNRTI first-line ART. Methods We conducted a case–control study of 170 adults with HIV-1/TB co-infection. Cases had at least one viral load (VL) ≥1000 RNA copies/mL after ≥6 months on NNRTI-based ART, and controls had sustained VLs <1000 copies/mL. We sequenced plasma viruses by Sanger and MiSeq next-generation sequencing (NGS). We assessed drug resistance mutations (DRMs) using the Stanford drug resistance database, and analysed NGS data for DRMs at ≥20%, 10%, 5% and 2% thresholds. We assessed the effect of pretreatment drug resistance (PDR) on VF. Results We analysed sequences from 45 cases and 125 controls. Overall prevalence of PDR detected at a ≥20% threshold was 4.7% (8/170) and was higher in cases than in controls (8.9% versus 3.2%), P = 0.210. Participants with PDR at ≥20% had almost 4-fold higher odds of VF (adjusted OR 3.7, 95% CI 0.8–18.3) compared with those without, P = 0.104. PDR prevalence increased to 18.2% (31/170) when LA-DRVs at ≥2% were included. Participants with pretreatment LA-DRVs only had 1.6-fold higher odds of VF (adjusted OR 1.6, 95% CI 0.6–4.3) compared with those without, P = 0.398. Conclusions Pretreatment DRMs and LA-DRVs increased the odds of developing VF on NNRTI-based ART, although without statistical significance. NGS increased detection of DRMs but provided no additional benefit in identifying participants at risk of VF at lower thresholds. More studies assessing mutation thresholds predictive of VF are required to inform use of NGS in treatment decisions.

scholarly journals Antimicrobial drug resistance and infection prevention/control: lessons from tuberculosis

2021 ◽  
Author(s):  
J. Peter Cegielski ◽  
Carrie Tudor ◽  
Grigory V. Volchenkov ◽  
Paul A. Jensen
Keyword(s):  
Public Health ◽  
Drug Resistance ◽  
Infection Prevention ◽  
Antimicrobial Drug ◽  
Infection Prevention And Control ◽  
Drug Resistant ◽  
Drug Resistant Tuberculosis ◽  
Antimicrobial Drug Resistance ◽  
The Past ◽  
Resistant Tuberculosis

Antimicrobial drug resistance (AMR) is increasing rapidly worldwide, causing an estimated 700,000 deaths annually over the past decade, en route to becoming the leading global threat to public health by 2050 with an estimated 10 million deaths per year (more than heart disease, cancer, and stroke), while reducing global wealth by US$100 trillion. Yet AMR has not received the attention and action required to change this trajectory. Appropriate infection prevention and control (IPC) measures are needed to prevent transmission of infections to healthcare workers (HCWs), other patients, families, and the general public. In this review, we discuss a notable case study of AMR: highly drug-resistant tuberculosis (TB) has emerged repeatedly over the past 70 years as new drugs have been introduced, leading to new diagnostics, therapeutics, funding, public health strategies, and, in high-income countries, effective IPC measures that curtailed transmission. We review current efforts to control and prevent AMR using the example of drug-resistant tuberculosis to highlight important themes including laboratory systems, surveillance, control and prevention of healthcare-associated infections (especially among HCWs), better coordination across disciplines and diseases, and powerful advocacy/social change initiatives grounded in social and behavioral sciences. These strategies are the foundation of an effective response to the AMR threat to public health.

scholarly journals Resistance at No Cost: The Transmissibility and Potential for Disease Progression of Drug-ResistantM. Tuberculosis

2018 ◽  
Author(s):  
Mercedes C. Becerra ◽  
Chuan-Chin Huang ◽  
Leonid Lecca ◽  
Jaime Bayona ◽  
Carmen Contreras ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Drug Resistant ◽  
Resistance Mutations ◽  
Pulmonary Tb ◽  
Genetic Fingerprint ◽  
Resistant Tuberculosis ◽  
Significant Difference ◽  
Mdr Tb ◽  
The Impact

AbstractBackgroundThe future trajectory of drug resistant tuberculosis strongly depends on the fitness costs of drug resistance mutations. Here, we measured the association of phenotypic drug resistance and the risk of TB infection and disease among household contacts (HHCs) of patients with pulmonary TB.MethodsWe evaluated 12767 HHCs of patients with drug sensitive and resistant pulmonary TB at baseline, two, six, and 12 months to ascertain infection status and to determine whether they developed tuberculosis disease. We also assessed the impact of drug resistance phenotype on the likelihood that a TB strain shared a genetic fingerprint with at least one other TB patient in the cohort.FindingsAmong 3339 TB patients for whom were DST available, 1274 (38%) had TB that was resistant to at least one drug and 478 (14⋅3%) had multi-drug resistant (MDR) TB, i.e. TB resistant to both INH and rifampicin. Compared to HHCs of drug sensitive TB patients, those exposed to a patient with MDR-TB had an 8% (95% CI: 4-13%) higher risk of infection by the end of follow up. We found no statistically significant difference in the relative hazard of incident TB disease among HHCs exposed to MDR-TB compared to DS-TB (Adjusted HR 1⋅28 [(95% CI: ⋅9-1⋅83]). Patients with MDR-TB were more likely to be part of a genetic cluster than were DS-TB patients.InterpretationClinical strains of MDR M. tuberculosis are neither less transmissible than drug sensitive strains nor less likely to cause disease. (ClinicalTrials.gov number,NCT00676754)FundingNational Institutes of Health: NIH/NIAID CETR U19AI109755StatementAll authors have seen the manuscript and approved the manuscript.

Surveillance of the Antimicrobial Resistance Rates of Helicobacter pylori Ten Years Later in the Western Central Region, Colombia

2019 ◽  
Vol 38 (3) ◽  
pp. 196-203
Author(s):  
Ingrid Johanna Bedoya-Gómez ◽  
Adalucy Alvarez-Aldana ◽  
José Ignacio Moncayo-Ortiz ◽  
Yina Marcela Guaca-González ◽  
Jorge Javier Santacruz-Ibarra ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Helicobacter Pylori ◽  
Antimicrobial Drug ◽  
Test Method ◽  
Clinical Isolates ◽  
Moderate Increase ◽  
Antimicrobial Drugs ◽  
Antimicrobial Drug Resistance ◽  
H Pylori ◽  
Resistance Rates

Background: Helicobacter pylori is a bacterium associated with gastroduodenal disease and gastric cancer. Empirical therapy in the treatment of H. pylori infection increases the risk of apparition of antimicrobial drug resistance. In a previous report, in H. pylori clinical isolates, resistance rates to commonly used antimicrobial drugs were as follows: metronidazole 82%, clarithromycin 3.8%, and amoxicillin 1.9%. The aim was to establish the variation of resistance rates and the detection of H. pylori genetic mutations isolated from dyspeptic patients. Methods: Antimicrobial susceptibility profiles were performed by the E-test method for metronidazole, clarithromycin, amoxicillin, and tetracycline in 61 clinical isolates. Sequencing was performed to detect mutations associated with resistance to clarithromycin. Results: According to our results, resistance rates found in the 61 isolates were 78.60% for metronidazole and 8.20% for clarithromycin. None of the studied isolates had resistance to tetracycline and amoxicillin. Secondary resistance rates displayed an increase when compared to primary rates for metronidazole (87.50 vs. 77.35%) and for clarithromycin (25.66 vs. 5.66%). Of 5 isolates resistant to clarithromycin, 3 had the A2143G mutation. By comparing the results in this work with previous reports, antimicrobial drug resistance rates did not show major modifications for metronidazole, amoxicillin, and tetracycline during the last 10 years. For clarithromycin, the resistance rate showed a moderate increase; nevertheless, it remains low (<15%) and this change was not statistically significant. Conclusion: Together, all findings in this work indicate that these antimicrobial drugs can still be used as first line of defense on infected patients living in this region of the country.

Drug Resistance and Dormancy Represent Reversible Characteristics in Patients' ALL Cells Growing in Mice

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 602-602
Author(s):  
Erbey Ziya Özdemir ◽  
Sarah Ebinger ◽  
Christoph Ziegenhain ◽  
Wolfgang Enard ◽  
Olivier Gires ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Drug Resistance ◽  
Treatment Strategies ◽  
Preclinical Model ◽  
Bone Marrow Niche ◽  
Drug Resistant ◽  
Novel Treatment ◽  
Dormant Cells

Abstract Introduction Drug resistant cells represent a major threat for tumor patients as they might induce relapse and severely decrease disease outcome. Relapse represents a major drawback in patients with acute lymphoblastic leukemia (ALL), the single most frequent malignancy in children. Novel treatment options are intensively desired to remove drug resistant cells, which often additionally display dormancy. Aim We aimed at unraveling basic mechanisms determining drug resistance and dormancy, as basis for developing novel treatment strategies to prevent relapse. Methods Using cutting edge in vivo technology, we performed genetic engineering in the individualized xenograft mouse model of ALL. Primary patients' ALL cells were amplified in mice to generate patient-derived xenograft (PDX) cells. ALL PDX cells were lentivirally transduced to express transgenes. Recombinant luciferase allowed highly sensitive and reliable follow-up of leukemia growth and treatment. Recombinant surface markers enabled an unbiased approach to reliably and effectively enriching minute numbers of PDX cells from mouse bone marrow. Two independent, complementary innovative preclinical in vivo mouse models were established.In the first model, proliferation sensitive dyes allowed identifying and enriching in vivo long-term dormant PDX ALL cells.In the second model, the clinically highly relevant and challenging situation of MRD was mimicked in mice. PDX ALL cells were grown to advanced leukemia stages of above 30 % human blasts in bone marrow, when systemic chemotherapy with conventional cytotoxic drugs was initiated for prolonged periods of time, similar as applied in ALL patients. Chemotherapy reduced advanced leukemia down to 0,1 % or 10-3 leukemia cells in bone marrow, resembling not only complete morphologic remission, but even molecular remission. This novel preclinical model allows for the first time to characterize patients' dormant and MRD cells in detail including functional in vivo assays. Results Using our innovative preclinical model of dormancy, we identified a novel, distinct, rare subpopulation of PDX ALL cells that displayed long term dormancy in vivo. Long-term dormant cells showed significant resistance against drug treatment in vivo, as therapy nearly exclusively targeted proliferating cells. Dormant cells showed stem cell behavior as they initiated leukemia upon re-transplantation into further recipient mice. Long-term dormant cells thus combined the three challenging characteristics of relapse-inducing cells dormancy, drug resistance and stemness with re-growth upon withdrawal of treatment pressure. Using our second novel preclinical model, we isolated a pure, vivid fraction of rare MRD cells. These cells showed drug resistance in vivo and stemness features. We used single cell RNA sequencing to compare the transcriptomes of dormant and MRD populations and found that they were highly similar. Both populations had further similarities with primary high-risk ALL cells and dormant sub-fractions in patients' leukemia samples. Of high relevance for future treatment strategies, both, dormancy and drug resistance revealed transient characteristics in PDX ALL cells. When PDX long-term dormant ALL cells were distracted from their in vivo environment, they started proliferating similarly as their previously highly proliferative counterparts. When in vivo drug resistant PDX ALL cells were retrieved from murine bone marrow, they showed similar drug sensitivity in vitro as their sensitive counterparts. Summary/Conclusion Thus, both in vivo dormancy and drug resistance represent reversible characteristics in ALL cells which might result from the localization of ALL cells in the bone marrow niche. Dissolving ALL cells from their in vivo environment might sensitize them towards treatment. Addressing and inhibiting the interaction between ALL cells and their bone marrow niche might represent an attractive future therapeutic strategy to prevent ALL relapse. Disclosures No relevant conflicts of interest to declare.

scholarly journals Evolution and Transmission Patterns of Extensively Drug-Resistant Tuberculosis in China

2014 ◽  
Vol 59 (2) ◽  
pp. 818-825 ◽  
Author(s):  
Feifei Wang ◽  
Lingyun Shao ◽  
Xiaoping Fan ◽  
Yaojie Shen ◽  
Ni Diao ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Resistance Genes ◽  
Variable Number Tandem Repeat ◽  
Resistance Mutation ◽  
Beijing Genotype ◽  
Drug Resistant ◽  
Resistance Mutations ◽  
Drug Resistant Tuberculosis ◽  
Resistant Tuberculosis ◽  
Extensively Drug Resistant

ABSTRACTThe emergence and transmission of extensively drug-resistant tuberculosis (XDR-TB) pose an increasing threat to global TB control. This study aimed to identify the patterns of evolution and transmission dynamics of XDR-TB in populations in a region of China where TB is highly endemic. We analyzed a total of 95 XDR-TB isolates collected from 2003 to 2009 in Chongqing, China. Eight drug resistance genes covering 7 drugs that define XDR-TB were amplified by PCR followed by DNA sequencing. Variable-number tandem repeat 16-locus (VNTR-16) genotyping and genotypic drug resistance profiles were used to determine the evolution or transmission patterns of XDR-TB strains. Our results indicated that the Beijing genotype was predominant (85/95 [89.5%]) in XDR-TB strains, and as many as 40.0% (38/95) of the isolates were distributed into 6 clusters based on VNTR-16 genotyping and drug resistance mutation profiles. All isolates of each cluster harbored as many as six identical resistance mutations in the drug resistance genesrpoB,katG,inhApromoter,embB,rpsL, andgidB. Among the nine cases with continuous isolates from multidrug-resistant (MDR) to XDR-TB, 4 cases represented acquired drug resistance, 4 cases were caused by transmission, and 1 case was due to exogenous superinfection. The XDR-TB epidemic in China is mainly caused by a high degree of clonal transmission, but evolution from MDR to XDR and even superinfection with a new XDR strain can also occur.

scholarly journals Evolution of Fluconazole-ResistantCandida albicansStrains by Drug-Induced Mating Competence and Parasexual Recombination

mBio ◽  
2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Christina Popp ◽  
Bernardo Ramírez-Zavala ◽  
Sonja Schwanfelder ◽  
Ines Krüger ◽  
Joachim Morschhäuser
Keyword(s):  
Drug Resistance ◽  
Mating Type ◽  
Acquired Resistance ◽  
Resistance Mechanisms ◽  
Drug Resistant ◽  
Resistance Mutations ◽  
Type Locus ◽  
Content Type ◽  
Mating Type Locus ◽  
Resistant Progeny

ABSTRACTThe clonal population structure ofCandida albicanssuggests that (para)sexual recombination does not play an important role in the lifestyle of this opportunistic fungal pathogen, an assumption that is strengthened by the fact that mostC. albicansstrains are heterozygous at the mating type locus (MTL) and therefore mating-incompetent. On the other hand, mating might occur within clonal populations and allow the combination of advantageous traits that were acquired by individual cells to adapt to adverse conditions. We have investigated if parasexual recombination may be involved in the evolution of highly drug-resistant strains exhibiting multiple resistance mechanisms against fluconazole, an antifungal drug that is commonly used to treat infections byC. albicans. Growth of strains that were heterozygous forMTLand different fluconazole resistance mutations in the presence of the drug resulted in the emergence of derivatives that had become homozygous for the mutated allele and the mating type locus and exhibited increased drug resistance. WhenMTLa/aandMTLα/α cells of these strains were mixed in all possible combinations, we could isolate mating products containing the genetic material from both parents. The initial mating products did not exhibit higher drug resistance than their parental strains, but further propagation under selective pressure resulted in the loss of the wild-type alleles and increased fluconazole resistance. Therefore, fluconazole treatment not only selects for resistance mutations but also promotes genomic alterations that confer mating competence, which allows cells in an originally clonal population to exchange individually acquired resistance mechanisms and generate highly drug-resistant progeny.IMPORTANCESexual reproduction is an important mechanism in the evolution of species, since it allows the combination of advantageous traits of individual members in a population. The pathogenic yeastCandida albicansis a diploid organism that normally propagates in a clonal fashion, because heterozygosity at the mating type locus (MTL) inhibits mating between cells. Here we show thatC. albicanscells that have acquired drug resistance mutations during treatment with the commonly used antifungal agent fluconazole rapidly develop further increased resistance by genome rearrangements that result in simultaneous loss of heterozygosity for the mutated allele and the mating type locus. This enables the drug-resistant cells of a population to switch to the mating-competent opaque morphology and mate with each other to combine different individually acquired resistance mechanisms. The tetraploid mating products reassort their merged genomes and, under selective pressure by the drug, generate highly resistant progeny that have retained the advantageous mutated alleles. Parasexual propagation, promoted by stress-induced genome rearrangements that result in the acquisition of mating competence in cells with adaptive mutations, may therefore be an important mechanism in the evolution ofC. albicanspopulations.

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