scholarly journals Effects of antibiotic resistance alleles on bacterial evolutionary responses to viral parasites

2016 ◽  
Vol 12 (5) ◽  
pp. 20160064 ◽  
Author(s):  
Flor I. Arias-Sánchez ◽  
Alex R. Hall
Keyword(s):  
Antibiotic Resistance ◽  
Population Density ◽  
Phage Resistance ◽  
Antibiotic Resistant ◽  
Relative Growth ◽  
Resistance Evolution ◽  
Mutator Allele ◽  
Evolution Of Resistance ◽  
Positive Effect ◽  
Resistant Genotypes

Antibiotic resistance has wide-ranging effects on bacterial phenotypes and evolution. However, the influence of antibiotic resistance on bacterial responses to parasitic viruses remains unclear, despite the ubiquity of such viruses in nature and current interest in therapeutic applications. We experimentally investigated this by exposing various Escherichia coli genotypes, including eight antibiotic-resistant genotypes and a mutator, to different viruses (lytic bacteriophages). Across 960 populations, we measured changes in population density and sensitivity to viruses, and tested whether variation among bacterial genotypes was explained by their relative growth in the absence of parasites, or mutation rate towards phage resistance measured by fluctuation tests for each phage. We found that antibiotic resistance had relatively weak effects on adaptation to phages, although some antibiotic-resistance alleles impeded the evolution of resistance to phages via growth costs. By contrast, a mutator allele, often found in antibiotic-resistant lineages in pathogenic populations, had a relatively large positive effect on phage-resistance evolution and population density under parasitism. This suggests costs of antibiotic resistance may modify the outcome of phage therapy against pathogenic populations previously exposed to antibiotics, but the effects of any co-occurring mutator alleles are likely to be stronger.

scholarly journals A trimethoprim derivative impedes antibiotic resistance evolution

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

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

scholarly journals Phage steering of antibiotic-resistance evolution in the bacterial pathogen, Pseudomonas aeruginosa

2020 ◽  
Vol 2020 (1) ◽  
pp. 148-157 ◽  
Author(s):  
James Gurney ◽  
Léa Pradier ◽  
Joanne S Griffin ◽  
Claire Gougat-Barbera ◽  
Benjamin K Chan ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antibiotic Resistance ◽  
Bacterial Pathogen ◽  
Antibiotic Sensitivity ◽  
Resistant Bacteria ◽  
Phage Resistance ◽  
Antibiotic Resistant ◽  
Trade Off

Abstract Background and objectives Antimicrobial resistance is a growing global concern and has spurred increasing efforts to find alternative therapeutics. Bacteriophage therapy has seen near constant use in Eastern Europe since its discovery over a century ago. One promising approach is to use phages that not only reduce bacterial pathogen loads but also select for phage resistance mechanisms that trade-off with antibiotic resistance—so called ‘phage steering’. Methodology Recent work has shown that the phage OMKO1 can interact with efflux pumps and in so doing select for both phage resistance and antibiotic sensitivity of the pathogenic bacterium Pseudomonas aeruginosa. We tested the robustness of this approach to three different antibiotics in vitro (tetracycline, erythromycin and ciprofloxacin) and one in vivo (erythromycin). Results We show that in vitro OMKO1 can reduce antibiotic resistance of P. aeruginosa (Washington PAO1) even in the presence of antibiotics, an effect still detectable after ca.70 bacterial generations in continuous culture with phage. Our in vivo experiment showed that phage both increased the survival times of wax moth larvae (Galleria mellonella) and increased bacterial sensitivity to erythromycin. This increased antibiotic sensitivity occurred both in lines with and without the antibiotic. Conclusions and implications Our study supports a trade-off between antibiotic resistance and phage sensitivity. This trade-off was maintained over co-evolutionary time scales even under combined phage and antibiotic pressure. Similarly, OMKO1 maintained this trade-off in vivo, again under dual phage/antibiotic pressure. Our findings have implications for the future clinical use of steering in phage therapies. Lay Summary: Given the rise of antibiotic-resistant bacterial infection, new approaches to treatment are urgently needed. Bacteriophages (phages) are bacterial viruses. The use of such viruses to treat infections has been in near-continuous use in several countries since the early 1900s. Recent developments have shown that these viruses are not only effective against routine infections but can also target antibiotic resistant bacteria in a novel, unexpected way. Similar to other lytic phages, these so-called ‘steering phages’ kill the majority of bacteria directly. However, steering phages also leave behind bacterial variants that resist the phages, but are now sensitive to antibiotics. Treatment combinations of these phages and antibiotics can now be used to greater effect than either one independently. We evaluated the impact of steering using phage OMKO1 and a panel of three antibiotics on Pseudomonas aeruginosa, an important pathogen in hospital settings and in people with cystic fibrosis. Our findings indicate that OMKO1, either alone or in combination with antibiotics, maintains antibiotic sensitivity both in vitro and in vivo, giving hope that phage steering will be an effective treatment option against antibiotic-resistant bacteria.

scholarly journals Targeting antibiotic resistant bacteria with phage reduces bacterial density in an insect host

2019 ◽  
Vol 15 (3) ◽  
pp. 20180895 ◽  
Author(s):  
Lauri Mikonranta ◽  
Angus Buckling ◽  
Matti Jalasvuori ◽  
Ben Raymond
Keyword(s):  
Antibiotic Resistance ◽  
Phage Therapy ◽  
Synergistic Effects ◽  
Low Frequency ◽  
Resistant Bacteria ◽  
Antibiotic Resistant ◽  
Model Studies ◽  
Evolution Of Resistance ◽  
Insect Gut

Phage therapy is attracting growing interest among clinicians as antibiotic resistance continues becoming harder to control. However, clinical trials and animal model studies on bacteriophage treatment are still scarce and results on the efficacy vary. Recent research suggests that using traditional antimicrobials in concert with phage could have desirable synergistic effects that hinder the evolution of resistance. Here, we present a novel insect gut model to study phage–antibiotic interaction in a system where antibiotic resistance initially exists in very low frequency and phage specifically targets the resistance bearing cells. We demonstrate that while phage therapy could not reduce the frequency of target bacteria in the population during positive selection by antibiotics, it alleviated the antibiotic induced blooming by lowering the overall load of resistant cells. The highly structured gut environment had pharmacokinetic effects on both phage and antibiotic dynamics compared with in vitro : antibiotics did not reduce the overall amount of bacteria, demonstrating a simple turnover of gut microbiota from non-resistant to resistant population with little cost. The results imply moderate potential for using phage as an aid to target antibiotic resistant gut infections, and question the usefulness of in vitro inferences.

scholarly journals Associations among Antibiotic and Phage Resistance Phenotypes in Natural and Clinical Escherichia coli Isolates

mBio ◽  
2017 ◽  
Vol 8 (5) ◽  
Author(s):  
Richard C. Allen ◽  
Katia R. Pfrunder-Cardozo ◽  
Dominik Meinel ◽  
Adrian Egli ◽  
Alex R. Hall
Keyword(s):  
Escherichia Coli ◽  
Antibiotic Resistance ◽  
Bacterial Infections ◽  
Antibacterial Agents ◽  
Core Genome ◽  
Bacterial Genome ◽  
Abundant Species ◽  
Phage Resistance ◽  
Resistance Evolution ◽  
Genome Phylogeny

ABSTRACT The spread of antibiotic resistance is driving interest in new approaches to control bacterial pathogens. This includes applying multiple antibiotics strategically, using bacteriophages against antibiotic-resistant bacteria, and combining both types of antibacterial agents. All these approaches rely on or are impacted by associations among resistance phenotypes (where bacteria resistant to one antibacterial agent are also relatively susceptible or resistant to others). Experiments with laboratory strains have shown strong associations between some resistance phenotypes, but we lack a quantitative understanding of associations among antibiotic and phage resistance phenotypes in natural and clinical populations. To address this, we measured resistance to various antibiotics and bacteriophages for 94 natural and clinical Escherichia coli isolates. We found several positive associations between resistance phenotypes across isolates. Associations were on average stronger for antibacterial agents of the same type (antibiotic-antibiotic or phage-phage) than different types (antibiotic-phage). Plasmid profiles and genetic knockouts suggested that such associations can result from both colocalization of resistance genes and pleiotropic effects of individual resistance mechanisms, including one case of antibiotic-phage cross-resistance. Antibiotic resistance was predicted by core genome phylogeny and plasmid profile, but phage resistance was predicted only by core genome phylogeny. Finally, we used observed associations to predict genes involved in a previously uncharacterized phage resistance mechanism, which we verified using experimental evolution. Our data suggest that susceptibility to phages and antibiotics are evolving largely independently, and unlike in experiments with lab strains, negative associations between antibiotic resistance phenotypes in nature are rare. This is relevant for treatment scenarios where bacteria encounter multiple antibacterial agents. IMPORTANCE Rising antibiotic resistance is making it harder to treat bacterial infections. Whether resistance to a given antibiotic spreads or declines is influenced by whether it is associated with altered susceptibility to other antibiotics or other stressors that bacteria encounter in nature, such as bacteriophages (viruses that infect bacteria). We used natural and clinical isolates of Escherichia coli, an abundant species and key pathogen, to characterize associations among resistance phenotypes to various antibiotics and bacteriophages. We found associations between some resistance phenotypes, and in contrast to past work with laboratory strains, they were exclusively positive. Analysis of bacterial genome sequences and horizontally transferred genetic elements (plasmids) helped to explain this, as well as our finding that there was no overall association between antibiotic resistance and bacteriophage resistance profiles across isolates. This improves our understanding of resistance evolution in nature, potentially informing new rational therapies that combine different antibacterials, including bacteriophages. IMPORTANCE Rising antibiotic resistance is making it harder to treat bacterial infections. Whether resistance to a given antibiotic spreads or declines is influenced by whether it is associated with altered susceptibility to other antibiotics or other stressors that bacteria encounter in nature, such as bacteriophages (viruses that infect bacteria). We used natural and clinical isolates of Escherichia coli, an abundant species and key pathogen, to characterize associations among resistance phenotypes to various antibiotics and bacteriophages. We found associations between some resistance phenotypes, and in contrast to past work with laboratory strains, they were exclusively positive. Analysis of bacterial genome sequences and horizontally transferred genetic elements (plasmids) helped to explain this, as well as our finding that there was no overall association between antibiotic resistance and bacteriophage resistance profiles across isolates. This improves our understanding of resistance evolution in nature, potentially informing new rational therapies that combine different antibacterials, including bacteriophages.

scholarly journals Competition and diversity determine vaccine impact on antibiotic resistance evolution

2019 ◽  
Author(s):  
Nicholas G. Davies ◽  
Stefan Flasche ◽  
Mark Jit ◽  
Katherine E. Atkins
Keyword(s):  
Antibiotic Resistance ◽  
Pneumococcal Vaccination ◽  
Antibiotic Use ◽  
Relative Strength ◽  
Antibiotic Resistant ◽  
Resistance Evolution ◽  
Pneumococcal Carriage ◽  
Bacterial Transmission ◽  
Vaccine Impact ◽  
The Impact

Bacterial vaccines can protect recipients from contracting potentially antibiotic-resistant infections. But by altering the selective balance between sensitive and resistant strains, vaccines may also help suppress—or spread—antibiotic resistance among unvaccinated individuals. Predicting the outcome requires knowing the drivers of resistance evolution. Using mathematical modelling, we identify competition and diversity as key mediators of resistance evolution. Specifically, we show that the frequency of penicillin resistance in Streptococcus pneumoniae (pneumococcus) across 27 European countries can be explained by between-host diversity in antibiotic use, heritable diversity in pneumococcal carriage duration, or within-host competition. We use our calibrated model to predict the impact of universal pneumococcal vaccination upon the prevalence of carriage, incidence of disease, and frequency of resistance for S. pneumoniae. The relative strength and directionality of competition between resistant and sensitive pneumococcal strains determines whether vaccination promotes, inhibits, or has little effect on the evolution of antibiotic resistance. Finally, we find that differences in overall bacterial transmission and carriage alter predictions, suggesting that evidence-based policies for managing resistance with vaccines must be tailored to both pathogen and setting.One sentence summaryCompetition and diversity are key to antibiotic resistance evolution and determine whether vaccines will prevent or increase resistant infections.

scholarly journals Targeting antibiotic resistant bacteria with phages reduces bacterial density in an insect host

2018 ◽  
Author(s):  
Lauri Mikonranta ◽  
Angus Buckling ◽  
Matti Jalasvuori ◽  
Ben Raymond
Keyword(s):  
Antibiotic Resistance ◽  
Phage Therapy ◽  
Synergistic Effects ◽  
Low Frequency ◽  
Resistant Bacteria ◽  
Antibiotic Resistant ◽  
Model Studies ◽  
Evolution Of Resistance ◽  
Insect Gut

Phage therapy is attracting growing interest among clinicians as antibiotic resistance continues becoming harder to control. However, clinical trials and animal model studies on bacteriophage treatment are still scarce and results on the efficacy vary. Recent research suggests that using traditional antimicrobials in concert with phage could have desirable synergistic effects that hinder the evolution of resistance. Here, we present a novel insect gut model to study phage-antibiotic interaction in a system where antibiotic resistance initially exists in very low frequency and phage specifically targets the resistance bearing cells. We demonstrate that while phage therapy could not reduce the frequency of target bacteria in the population during positive selection by antibiotics, it alleviated the antibiotic induced blooming by lowering the overall load of resistant cells. The highly structured gut environment had pharmacokinetic effects on both phage and antibiotic dynamics compared to in vitro: antibiotics did not reduce the overall amount of bacteria, demonstrating a simple turnover of gut flora from non-resistant to resistant population with little cost. The results imply moderate potential for using phage as an aid to target antibiotic resistant gut infections, and question the usefulness of in vitro inferences.

scholarly journals Exploiting evolutionary trade-offs to combat antibiotic resistance

2020 ◽  
Author(s):  
Sergey Melnikov ◽  
David L. Stephens ◽  
Xian Fu ◽  
Hui Si Kwok ◽  
Jin-Tao Zhang ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Rapid Evolution ◽  
Genetic Alterations ◽  
Trna Synthetase ◽  
Molecular Defect ◽  
Antibiotic Resistant ◽  
Resistance Evolution ◽  
Growth Defects ◽  
Trade Offs ◽  
Resistant Cells

ABSTRACTAntibiotic resistance frequently evolves through fitness trade-offs in which the genetic alterations that confer resistance to a drug can also cause growth defects in resistant cells. Here, through experimental evolution in a microfluidics-based turbidostat, we demonstrate that antibiotic-resistant cells can be efficiently inhibited by amplifying the fitness costs associated with drug-resistance evolution. Using tavaborole-resistant E. coli as a model, we show that genetic mutations in leucyl-tRNA synthetase (that underlie tavaborole resistance) make resistant cells intolerant to norvaline, a chemical analog of leucine that is mistakenly used by tavaborole-resistant cells for protein synthesis. We then show that tavaborole-sensitive cells quickly outcompete tavaborole-resistant cells in the presence of norvaline due to the amplified cost of the molecular defect of tavaborole resistance. This finding illustrates a potentially generalizable approach for combating therapeutic resistance, prolonging the effectiveness of drugs and enabling the use of drugs that are no longer effective due to the rapid evolution of resistance.

scholarly journals Characterization of an Enterococcus faecalis Bacteriophage vB_EfaM_LG1 and Its Synergistic Effect With Antibiotic

2021 ◽  
Vol 11 ◽  
Author(s):  
Min Song ◽  
Dongmei Wu ◽  
Yang Hu ◽  
Haiyan Luo ◽  
Gongbo Li
Keyword(s):  
Antibiotic Resistance ◽  
Synergistic Effect ◽  
Enterococcus Faecalis ◽  
Bacterial Infections ◽  
Opportunistic Pathogen ◽  
Phage Resistance ◽  
Bacteriophage Therapy ◽  
Antibiotic Resistant ◽  
Short Period

Enterococcus faecalis is a Gram-positive opportunistic pathogen that could cause pneumonia and bacteremia in stroke patients. The development of antibiotic resistance in hospital-associated E. faecalis is a formidable public health threat. Bacteriophage therapy is a renewed solution to treat antibiotic-resistant bacterial infections. However, bacteria can acquire phage resistance quite quickly, which is a significant barrier to phage therapy. Here, we characterized a lytic E. faecalis bacteriophage Vb_EfaM_LG1 with lytic activity. Its genome did not contain antibiotic resistance or virulence genes. Vb_EfaM_LG1 effectively inhibits E. faecalis growth for a short period, and phage resistance developed within hours. However, the combination of antibiotics and phage has a tremendous synergistic effect against E. faecalis, prevents the development of phage resistance, and disrupts the biofilm efficiently. Our results show that the phage-antibiotic combination has better killing efficiency against E. faecalis.

scholarly journals Predicting drug resistance evolution: insights from antimicrobial peptides and antibiotics

2018 ◽  
Vol 285 (1874) ◽  
pp. 20172687 ◽  
Author(s):  
Guozhi Yu ◽  
Desiree Y. Baeder ◽  
Roland R. Regoes ◽  
Jens Rolff
Keyword(s):  
Public Health ◽  
Antibiotic Resistance ◽  
Antimicrobial Peptides ◽  
Lower Probability ◽  
Health Concerns ◽  
Drug Candidates ◽  
Resistance Evolution ◽  
Medical Microbiology ◽  
Evolution Of Resistance ◽  
Multicellular Organisms

Antibiotic resistance constitutes one of the most pressing public health concerns. Antimicrobial peptides (AMPs) of multicellular organisms are considered part of a solution to this problem, and AMPs produced by bacteria such as colistin are last-resort drugs. Importantly, AMPs differ from many antibiotics in their pharmacodynamic characteristics. Here we implement these differences within a theoretical framework to predict the evolution of resistance against AMPs and compare it to antibiotic resistance. Our analysis of resistance evolution finds that pharmacodynamic differences all combine to produce a much lower probability that resistance will evolve against AMPs. The finding can be generalized to all drugs with pharmacodynamics similar to AMPs. Pharmacodynamic concepts are familiar to most practitioners of medical microbiology, and data can be easily obtained for any drug or drug combination. Our theoretical and conceptual framework is, therefore, widely applicable and can help avoid resistance evolution if implemented in antibiotic stewardship schemes or the rational choice of new drug candidates.

scholarly journals Modified Antibiotic Adjuvant Ratios Can Slow and Steer the Evolution of Resistance: Co-amoxiclav as a Case Study

mBio ◽  
2019 ◽  
Vol 10 (5) ◽  
Author(s):  
Richard C. Allen ◽  
Sam P. Brown
Keyword(s):  
Antibiotic Resistance ◽  
Treatment Efficacy ◽  
Copy Number ◽  
Resistance Mechanisms ◽  
Plasmid Copy Number ◽  
Plasmid Copy ◽  
Content Type ◽  
Resistance Evolution ◽  
Evolution Of Resistance ◽  
Lactamase Inhibitor

ABSTRACT As antibiotic resistance spreads, developing sustainable methods to restore the efficacy of existing antibiotics is increasingly important. One widespread method is to combine antibiotics with synergistically acting adjuvants that inhibit resistance mechanisms, allowing drug killing. Here we use co-amoxiclav (a clinically important combination of the β-lactam antibiotic amoxicillin and the β-lactamase inhibitor clavulanate) to ask whether treatment efficacy and resistance evolution can be decoupled via component dosing modifications. A simple mathematical model predicts that different ratios of these two drug components can produce distinct evolutionary responses irrespective of the initial efficacy. We test this hypothesis by selecting Escherichia coli with a plasmid-encoded β-lactamase (CTX-M-14), against different concentrations of amoxicillin and clavulanate. Consistent with our theory, we found that while resistance evolved under all conditions, the component ratio influenced both the rate and mechanism of resistance evolution. Specifically, we found that the current clinical practice of high amoxicillin-to-clavulanate ratios resulted in the most rapid adaptation to antibiotics via gene dosing responses. Increased plasmid copy number allowed E. coli to increase β-lactamase dosing and effectively titrate out low quantities of clavulanate, restoring amoxicillin resistance. In contrast, high clavulanate ratios were more robust—plasmid copy number did not increase, although porin or efflux resistance mechanisms were found, as for all drug ratios. Our results indicate that by changing the ratio of adjuvant to antibiotic we can slow and steer the path of resistance evolution. We therefore suggest using increased adjuvant dosing regimens to slow the rate of resistance evolution. IMPORTANCE As antibiotic resistance spreads, a promising approach is to restore the effectiveness of existing drugs via coadministration with adjuvants that inhibit resistance. However, as for monotherapy, antibiotic-adjuvant therapies can select for a variety of resistance mechanisms, so it is imperative that adjuvants be used in a sustainable manner. We test whether the rate of resistance evolution can be decoupled from treatment efficacy using co-amoxiclav, a clinically important combination of the β-lactam amoxicillin and β-lactamase inhibitor clavulanate. Using experimental evolution and a simple theoretical model, we show that the current co-amoxiclav formulation with a high proportion of amoxicillin rapidly selects for resistance via increased β-lactamase production. On the other hand, formulations with more clavulanate and less amoxicillin have similar efficacies yet prevent the selective benefit of increased β-lactamase. We suggest that by blocking common paths to resistance, treatment combinations with the adjuvant in excess can slow the evolution of resistance.

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