scholarly journals Novel Insights into Selection for Antibiotic Resistance in Complex Microbial Communities

2018 ◽  
Author(s):  
Aimee K. Murray ◽  
Lihong Zhang ◽  
Xiaole Yin ◽  
Tong Zhang ◽  
Angus Buckling ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Microbial Communities ◽  
Single Species ◽  
Dependent Manner ◽  
Opportunistic Pathogens ◽  
Antibiotic Resistant ◽  
Naturally Occurring ◽  
Selection For ◽  
Antibiotic Degradation ◽  
Dose Dependent

ABSTRACTRecent research has demonstrated selection for antibiotic resistance occurs at very low antibiotic concentrations in single species experiments, but the relevance of these findings when species are embedded in complex microbial communities is unclear. We show the strength of selection for naturally occurring resistance alleles in a complex community remains constant from low sub-inhibitory to above clinically relevant concentrations. Selection increases with antibiotic concentration before reaching a plateau where selection remains constant over a two order magnitude concentration range. This is likely to be due to cross-protection of the susceptible bacteria in the community following rapid extracellular antibiotic degradation by the resistant population, shown experimentally through a combination of chemical quantification and bacterial growth experiments. Metagenome and 16S rRNA analyses on sewage-derived bacterial communities evolved under cefotaxime exposure show preferential enrichment forblaCTX-Mgenes over all other beta-lactamase genes, as well as positive selection and co-selection for antibiotic resistant, opportunistic pathogens. These findings have far reaching implications for our understanding of the evolution of antibiotic resistance, by challenging the long-standing assumption that selection occurs in a dose-dependent manner.

scholarly journals Novel Insights into Selection for Antibiotic Resistance in Complex Microbial Communities

mBio ◽  
2018 ◽  
Vol 9 (4) ◽  
Author(s):  
Aimee K. Murray ◽  
Lihong Zhang ◽  
Xiaole Yin ◽  
Tong Zhang ◽  
Angus Buckling ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Microbial Communities ◽  
Single Species ◽  
Dependent Manner ◽  
Antibiotic Concentration ◽  
Antibiotic Resistant ◽  
Global Issues ◽  
Clinical Environments ◽  
Selection For ◽  
Antibiotic Degradation

ABSTRACTRecent research has demonstrated that selection for antibiotic resistance occurs at very low antibiotic concentrations in single-species experiments, but the relevance of these findings when species are embedded in complex microbial communities is unclear. We show that the strength of selection for naturally occurring resistance alleles in a complex community remains constant from low subinhibitory to above clinically relevant concentrations. Selection increases with antibiotic concentration before reaching a plateau where selection remains constant over a 2-order-magnitude concentration range. This is likely to be due to cross protection of the susceptible bacteria in the community following rapid extracellular antibiotic degradation by the resistant population, shown experimentally through a combination of chemical quantification and bacterial growth experiments. Metagenome and 16S rRNA analyses of sewage-derived bacterial communities evolved under cefotaxime exposure show preferential enrichment forblaCTX-Mgenes over all other beta-lactamase genes, as well as positive selection and co-selection for antibiotic resistant, opportunistic pathogens. These findings have far-reaching implications for our understanding of the evolution of antibiotic resistance, by challenging the long-standing assumption that selection occurs in a dose-dependent manner.IMPORTANCEAntibiotic resistance is one of the greatest global issues facing society. Still, comparatively little is known about selection for resistance at very low antibiotic concentrations. We show that the strength of selection for clinically important resistance genes within a complex bacterial community can remain constant across a large antibiotic concentration range (wide selective space). Therefore, largely understudied ecological compartments could be just as important as clinical environments for selection of antibiotic resistance.

scholarly journals Bacterial defenses against a natural antibiotic promote collateral resilience to clinical antibiotics

2020 ◽  
Author(s):  
Lucas A. Meirelles ◽  
Elena K. Perry ◽  
Megan Bergkessel ◽  
Dianne K. Newman
Keyword(s):  
Antibiotic Resistance ◽  
Opportunistic Pathogen ◽  
Antimicrobial Treatment ◽  
Bacterial Survival ◽  
Human Pathogens ◽  
Opportunistic Pathogens ◽  
Chronic Infections ◽  
Antibiotic Resistant ◽  
Lung Infections ◽  
Environmental Microbes

SummaryAs antibiotic-resistant infections become increasingly prevalent worldwide, understanding the factors that lead to antimicrobial treatment failure is essential to optimizing the use of existing drugs. Opportunistic human pathogens in particular typically exhibit high levels of intrinsic antibiotic resistance and tolerance1, leading to chronic infections that can be nearly impossible to eradicate2. We asked whether the recalcitrance of these organisms to antibiotic treatment could be driven in part by their evolutionary history as environmental microbes, which frequently produce or encounter natural antibiotics3,4. Using the opportunistic pathogen Pseudomonas aeruginosa as a model, we demonstrate that the self-produced natural antibiotic pyocyanin (PYO) activates bacterial defenses that confer collateral tolerance to certain synthetic antibiotics, including in a clinically-relevant growth medium. Non-PYO-producing opportunistic pathogens isolated from lung infections similarly display increased antibiotic tolerance when they are co-cultured with PYO-producing P. aeruginosa. Furthermore, we show that beyond promoting bacterial survival in the presence of antibiotics, PYO can increase the apparent rate of mutation to antibiotic resistance by up to two orders of magnitude. Our work thus suggests that bacterial production of natural antibiotics in infections could play an important role in modulating not only the immediate efficacy of clinical antibiotics, but also the rate at which antibiotic resistance arises in multispecies bacterial communities.

scholarly journals Acetylcholinesterase and Butyrylcholinesterase Inhibitory Compounds from Chelidonium Majus (Papaveraceae)

2010 ◽  
Vol 5 (11) ◽  
pp. 1934578X1000501 ◽  
Author(s):  
Lucie Cahlíková ◽  
Lubomír Opletal ◽  
Milan Kurfürst ◽  
Kateřina Macáková ◽  
Andrea Kulhánková ◽  
...  
Keyword(s):  
Human Plasma ◽  
Human Blood ◽  
Inhibitory Activity ◽  
Dependent Manner ◽  
Isoquinoline Alkaloids ◽  
Chelidonium Majus ◽  
Aerial Parts ◽  
Naturally Occurring ◽  
Inhibitory Compounds ◽  
Dose Dependent

The roots and aerial parts of Chelidonium majus L. were extracted with EtOH and fractionated using CHCl3 and EtOH. Repeated column chromatography, preparative TLC and crystallization led to the isolation of five isoquinoline alkaloids, stylopine (3), chelidonine (4), homochelidonine (5), protopine (6), and allocryptopine (7), along with two isolation artifacts 6-ethoxydihydrosanguinarine (1) and 6-ethoxydihydrochelerythrine (2). All isolated compounds were tested for human blood acetylcholinesterase (HuAChE) and human plasma butyrylcholinesterase (HuBuChE) inhibitory activity. The isolation artifacts exhibited the highest activity against HuAChE and HuBuChE with IC50 values of 0.83 ± 0.04 μM and 4.20 ± 0.19 μM for 6-ethoxydihydrochelerythrine and 3.25 ± 0.24 μM and 4.51 ± 0.31 μM for 6-ethoxydihydrosanguinarine. The most active of the naturally-occurring alkaloids was chelidonine, which inhibited both HuAChE and HuBuChE in a dose-dependent manner with IC50 values of 26.8 ± 1.2 μM and 31.9 ± 1.4 μM, respectively.

scholarly journals The antibiotic resistance of heterotrophic bacteria in tap waters in London

2018 ◽  
Vol 19 (1) ◽  
pp. 179-190
Author(s):  
R. Destiani ◽  
M. R. Templeton
Keyword(s):  
Antibiotic Resistance ◽  
Stenotrophomonas Maltophilia ◽  
Heterotrophic Bacteria ◽  
Tap Water ◽  
Antibiotic Resistance Genes ◽  
Resistant Bacteria ◽  
Opportunistic Pathogens ◽  
Antibiotic Resistant ◽  
Sampling Locations ◽  
The City

Abstract This study assessed the occurrence and prevalence of antibiotic-resistant bacteria (ARBs) and antibiotic resistance genes (ARGs) in tap water sampled across London, United Kingdom. Sampling was conducted seasonally from nine locations spread geographically across the city. ARBs and ARGs (tet(A), dfrA7, and sul1) were detected in all sampling locations in all sampling rounds. Resistance to trimethoprim was the highest among the tested antibiotics and the sul1 gene was the most abundant resistance gene detected. Several opportunistic pathogens were identified amongst the ARBs in the water samples, including Pseudomonas aeruginosa and Stenotrophomonas maltophilia.

scholarly journals Stress hormone masculinizes female morphology and behaviour

2010 ◽  
Vol 7 (1) ◽  
pp. 150-152 ◽  
Author(s):  
Rosemary Knapp ◽  
Edie Marsh-Matthews ◽  
Luanne Vo ◽  
Sarah Rosencrans
Keyword(s):  
Sexual Differentiation ◽  
Sex Steroids ◽  
Full Range ◽  
Reproductive Function ◽  
Morphological Characters ◽  
Sexually Dimorphic ◽  
Dependent Manner ◽  
Stress Hormone ◽  
Naturally Occurring ◽  
Dose Dependent

Sex steroids play major roles in vertebrate sexual differentiation. Unexpectedly, we now find that exposure to elevated levels of the naturally occurring stress hormone cortisol can also masculinize sexually dimorphic morphological characters and behaviour in adult female mosquitofish ( Gambusia affinis ) in a dose-dependent manner. Females masculinized by cortisol developed elongated anal fins with distal tip features similar to those of mature males. Most masculinized females also attempted to copulate when placed with normal females. Although the mechanism of masculinization is currently unknown, we propose a role for an enzyme that both inactivates cortisol and catalyzes the final step in synthesis of a major teleost androgen. This mechanism may also help explain some previously reported effects of stress on sexual development across vertebrate taxa. Our findings underscore the need to understand the full range of chemicals, both naturally occurring hormones and human-produced endocrine disruptors, that can influence sexual differentiation and reproductive function.

scholarly journals Selection for antibiotic resistance is reduced when embedded in a natural microbial community

2019 ◽  
Author(s):  
Uli Klümper ◽  
Mario Recker ◽  
Lihong Zhang ◽  
Xiaole Yin ◽  
Tong Zhang ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Microbial Community ◽  
Single Species ◽  
Natural Environments ◽  
Order Of Magnitude ◽  
Natural Microbial Community ◽  
Cost Of Resistance ◽  
Selection For ◽  
The Cost ◽  
Selection Of

AbstractAntibiotic resistance has emerged as one of the most pressing, global threats to public health. In single-species experiments selection for antibiotic resistance occurs at very low antibiotic concentrations. However, it is unclear how far these findings can be extrapolated to natural environments, where species are embedded within complex communities. We competed isogenic strains of Escherichia coli, differing exclusively in a single chromosomal resistance determinant, in the presence and absence of a pig fecal microbial community across a gradient of antibiotic concentration for two relevant antibiotics: gentamicin and kanamycin. We show that the minimal selective concentration was increased by more than one order of magnitude for both antibiotics when embedded in the community. We identified two general mechanisms were responsible for the increase in minimal selective concentration: an increase in the cost of resistance and a protective effect of the community for the susceptible phenotype. These findings have implications for our understanding of the evolution and selection of antibiotic resistance, and can inform future risk assessment efforts on antibiotic concentrations.

scholarly journals An adjunctive therapy administered with an antibiotic prevents enrichment of antibiotic-resistant clones of a colonizing opportunistic pathogen

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Valerie J Morley ◽  
Clare L Kinnear ◽  
Derek G Sim ◽  
Samantha N Olson ◽  
Lindsey M Jackson ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Bile Acid ◽  
Gastrointestinal Tract ◽  
Adjunctive Therapy ◽  
Opportunistic Pathogen ◽  
Proof Of Concept ◽  
Opportunistic Pathogens ◽  
Intravenous Antibiotic ◽  
Antibiotic Resistant ◽  
Fecal Shedding

A key challenge in antibiotic stewardship is figuring out how to use antibiotics therapeutically without promoting the evolution of antibiotic resistance. Here, we demonstrate proof of concept for an adjunctive therapy that allows intravenous antibiotic treatment without driving the evolution and onward transmission of resistance. We repurposed the FDA-approved bile acid sequestrant cholestyramine, which we show binds the antibiotic daptomycin, as an ‘anti-antibiotic’ to disable systemically-administered daptomycin reaching the gut. We hypothesized that adjunctive cholestyramine could enable therapeutic daptomycin treatment in the bloodstream, while preventing transmissible resistance emergence in opportunistic pathogens colonizing the gastrointestinal tract. We tested this idea in a mouse model of Enterococcus faecium gastrointestinal tract colonization. In mice treated with daptomycin, adjunctive cholestyramine therapy reduced the fecal shedding of daptomycin-resistant E. faecium by up to 80-fold. These results provide proof of concept for an approach that could reduce the spread of antibiotic resistance for important hospital pathogens.

scholarly journals Selection for Drug Resistance Results in Resistance to Fas-Mediated Apoptosis

Blood ◽  
1997 ◽  
Vol 89 (6) ◽  
pp. 1854-1861 ◽  
Author(s):  
Terry H. Landowski ◽  
Mary C. Gleason-Guzman ◽  
William S. Dalton
Keyword(s):  
Drug Resistance ◽  
Cell Lines ◽  
Antigen Expression ◽  
Lymphoid Cells ◽  
Dependent Manner ◽  
Chemotherapeutic Drugs ◽  
Mechanisms Of Resistance ◽  
Fas Antigen ◽  
Selection For ◽  
Dose Dependent

Abstract Recent evidence has supported the hypothesis that chemotherapeutic drugs and radiation induce an apoptotic pathway that requires the active participation of the cell. One pathway of apoptosis in malignant lymphoid cells is mediated by the Fas antigen. We studied the human myeloma (8226) and T-cell leukemia (CEM) cell lines selected for resistance to the anthracenes, doxorubicin or mitoxantrone, by continuous culture in the presence of either agent. We found that these drug-resistant cell lines were also resistant to Fas-mediated apoptosis in a dose-dependent manner. The degree of resistance to Fas-mediated apoptosis correlated directly with the level of resistance to chemotherapeutic drugs. These observations indicate that, as cancer cell lines develop mechanisms of drug resistance, they may also develop mechanisms of resistance to physiologic signals of apoptosis. Two mechanisms of resistance to Fas-mediated apoptosis were observed in these cell lines. One mechanism was associated with a dose-dependent reduction in the surface expression of Fas antigen. Analysis of RNA by reverse transcriptase-polymerase chain reaction assays showed that the reduction of Fas antigen expression occurred at the level of transcription. A second mechanism of drug resistance showed no decrease of Fas antigen expression; however, the apoptotic response was diminished. In this situation, removal of the chemotherapeutic agent resulted in a partial reversion to chemosensitivity and re-expression of the Fas antigen, but these cell lines did not regain the ability to undergo apoptosis in response to cross-linking by anti-Fas antibody. These findings support the hypothesis that apoptosis mediated by both chemotherapeutic agents and physiologic stimuli may share a common downstream effector. The demonstration that selection for drug resistance in hematopoietic cell lines results in a simultaneous resistance to Fas-mediated apoptosis may have clinical implications in the development of strategies for the treatment of resistant disease. Further analysis of the molecular mechanisms of Fas expression and function will facilitate the design of biological response modifying agents for the treatment of malignancy.

scholarly journals Naturally occurring human anti-band 3 autoantibodies accelerate clearance of erythrocytes in guinea pigs

Blood ◽  
1995 ◽  
Vol 85 (7) ◽  
pp. 1920-1928 ◽  
Author(s):  
U Giger ◽  
B Sticher ◽  
R Naef ◽  
R Burger ◽  
HU Lutz
Keyword(s):  
Guinea Pigs ◽  
Band 3 ◽  
Complement C3 ◽  
Erythrocyte Membranes ◽  
Dependent Manner ◽  
Band 3 Protein ◽  
Naturally Occurring ◽  
Dose Dependent

A variety of naturally occurring autoantibodies (NOAs) have been found in sera of animals and humans. Although their specific homeostatic role in the clearance of altered or senescent cells has been proposed and in vitro studies support such functions, in vivo evidence has been lacking. We studied the effect of affinity-purified human anti-band 3 NOA on the survival of untreated and diamide-treated erythrocytes in normal and complement C3-deficient guinea pigs. In vitro exposure to diamide, an oxidative agent, severely reduced the erythrocyte deformability and increased the amount of high-molecular-weight forms of band 3 protein and band 3-hemoglobin adducts in erythrocyte membranes, thereby markedly shortening the survival of these cells in vivo. Human anti-band 3 NOA bound in a dose-dependent manner to erythrocytes, and binding increased with exposure to diamide. In normal guinea pigs anti-band 3 NOA significantly accelerated the clearance of erythrocytes that were mildly damaged by iodine surface labeling and of those that were further oxidized by diamide. However, the anti-band 3 effect was transient and small. In contrast, anti-band 3 NOA did not significantly alter erythrocyte survival in functionally C3-deficient guinea pigs, thereby supporting the C3b requirement for anti-band 3 NOA activity. On the other hand, a pretreatment of animals with purified human band 3 protein slowed down the clearance of erythrocytes incubated with IgG depleted of anti-band 3 NOA. These results provide the first in vivo evidence of a role for anti-band 3 NOA in the clearance of erythrocytes.

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