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 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.

Impact of anthropogenic activities on the dissemination of antibiotic resistance across ecological boundaries

2017 ◽  
Vol 61 (1) ◽  
pp. 11-21 ◽  
Author(s):  
Vijay Tripathi ◽  
Eddie Cytryn
Keyword(s):  
Antibiotic Resistance ◽  
Microbial Communities ◽  
Anthropogenic Activities ◽  
Animal Husbandry ◽  
Resistant Bacteria ◽  
Human Pathogens ◽  
Antibiotic Resistant ◽  
Current State ◽  
Ecological Boundaries ◽  
Clinical Environments

Antibiotics are considered to be one of the major medical breakthroughs in history. Nonetheless, over the past four decades, antibiotic resistance has reached alarming levels worldwide and this trend is expected to continue to increase, leading some experts to forecast the coming of a ‘post-antibiotic’ era. Although antibiotic resistance in pathogens is traditionally linked to clinical environments, there is a rising concern that the global propagation of antibiotic resistance is also associated with environmental reservoirs that are linked to anthropogenic activities such as animal husbandry, agronomic practices and wastewater treatment. It is hypothesized that the emergence and dissemination of antibiotic-resistant bacteria (ARB) and antibiotic-resistant genes (ARGs) within and between environmental microbial communities can ultimately contribute to the acquisition of antibiotic resistance in human pathogens. Nonetheless, the scope of this phenomenon is not clear due to the complexity of microbial communities in the environment and methodological constraints that limit comprehensive in situ evaluation of microbial genomes. This review summarizes the current state of knowledge regarding antibiotic resistance in non-clinical environments, specifically focusing on the dissemination of antibiotic resistance across ecological boundaries and the contribution of this phenomenon to global antibiotic resistance.

scholarly journals Environmental Biofilms as Reservoirs for Antimicrobial Resistance

2021 ◽  
Vol 12 ◽  
Author(s):  
Gabriela Flores-Vargas ◽  
Jordyn Bergsveinson ◽  
John R. Lawrence ◽  
Darren R. Korber
Keyword(s):  
Antibiotic Resistance ◽  
Antimicrobial Resistance ◽  
Microbial Communities ◽  
Resistant Bacteria ◽  
Chemical Cue ◽  
Knowledge Gaps ◽  
Antibiotic Concentration ◽  
Antibiotic Resistant ◽  
Low Concentrations ◽  
The Impact

Characterizing the response of microbial communities to a range of antibiotic concentrations is one of the strategies used to understand the impact of antibiotic resistance. Many studies have described the occurrence and prevalence of antibiotic resistance in microbial communities from reservoirs such as hospitals, sewage, and farm feedlots, where bacteria are often exposed to high and/or constant concentrations of antibiotics. Outside of these sources, antibiotics generally occur at lower, sub-minimum inhibitory concentrations (sub-MICs). The constant exposure to low concentrations of antibiotics may serve as a chemical “cue” that drives development of antibiotic resistance. Low concentrations of antibiotics have not yet been broadly described in reservoirs outside of the aforementioned environments, nor is the transfer and dissemination of antibiotic resistant bacteria and genes within natural microbial communities fully understood. This review will thus focus on low antibiotic-concentration environmental reservoirs and mechanisms that are important in the dissemination of antibiotic resistance to help identify key knowledge gaps concerning the environmental resistome.

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 Widely Used Benzalkonium Chloride Disinfectants Can Promote Antibiotic Resistance

2018 ◽  
Vol 84 (17) ◽  
Author(s):  
Minjae Kim ◽  
Michael R. Weigand ◽  
Seungdae Oh ◽  
Janet K. Hatt ◽  
Raj Krishnan ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Microbial Communities ◽  
Gene Cloning ◽  
Benzalkonium Chloride ◽  
Efflux Pump ◽  
Resistant Bacteria ◽  
Antibiotic Resistant Bacteria ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Physiological Adaptations

ABSTRACTWhile the misuse of antibiotics has clearly contributed to the emergence and proliferation of resistant bacterial pathogens, with major health consequences, it remains less clear if the widespread use of disinfectants, such as benzalkonium chlorides (BAC), a different class of biocides than antibiotics, has contributed to this problem. Here, we provide evidence that exposure to BAC coselects for antibiotic-resistant bacteria and describe the underlying genetic mechanisms. After inoculation with river sediment, BAC-fed bioreactors selected for several bacterial taxa, including the opportunistic pathogenPseudomonas aeruginosa, that were more resistant to several antibiotics than their counterparts in a control (no BAC) bioreactor. A metagenomic analysis of the bioreactor microbial communities, confirmed by gene cloning experiments with the derived isolates, suggested that integrative and conjugative elements encoding a BAC efflux pump together with antibiotic resistance genes were responsible for these results. Furthermore, the exposure of theP. aeruginosaisolates to increasing concentrations of BAC selected for mutations inpmrB(polymyxin resistance) and physiological adaptations that contributed to a higher tolerance to polymyxin B and other antibiotics. The physiological adaptations included the overexpression ofmexCD-oprJmultidrug efflux pump genes when BAC was added in the growth medium at subinhibitory concentrations. Collectively, our results demonstrated that disinfectants promote antibiotic resistance via several mechanisms and highlight the need to remediate (degrade) disinfectants in nontarget environments to further restrain the spread of antibiotic-resistant bacteria.IMPORTANCEBenzalkonium chlorides (BAC) are biocides broadly used in disinfectant solutions. Disinfectants are widely used in food processing lines, domestic households, and pharmaceutical products and are typically designed to have a different mode of action than antibiotics to avoid interfering with the use of the latter. Whether exposure to BAC makes bacteria more resistant to antibiotics remains an unresolved issue of obvious practical consequences for public health. Using an integrated approach that combines metagenomics of natural microbial communities with gene cloning experiments with isolates and experimental evolution assays, we show that the widely used benzalkonium chloride disinfectants promote clinically relevant antibiotic resistance. Therefore, more attention should be given to the usage of these disinfectants, and their fate in nontarget environments should be monitored more tightly.

scholarly journals Combining antibiotics with antivirulence compounds can have synergistic effects and reverse selection for antibiotic resistance in Pseudomonas aeruginosa

2019 ◽  
Author(s):  
Chiara Rezzoagli ◽  
Martina Archetti ◽  
Ingrid Mignot ◽  
Michael Baumgartner ◽  
Rolf Kümmerli
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antibiotic Resistance ◽  
Synergistic Effects ◽  
Rapid Evolution ◽  
Resistance Mechanisms ◽  
Interaction Patterns ◽  
Systematic Analysis ◽  
Antibiotic Resistant ◽  
Drug Concentrations ◽  
Selection For

AbstractAntibiotics are losing efficacy due to the rapid evolution and spread of resistance. Treatments targeting bacterial virulence factors have been considered as alternatives because they target virulence instead of pathogen viability, and should therefore exert weaker selection for resistance than conventional antibiotics. However, antivirulence treatments rarely clear infections, which compromises their clinical applications. Here, we explore the potential of combining antivirulence drugs with antibiotics against the opportunistic human pathogen Pseudomonas aeruginosa. We combined two antivirulence compounds (gallium, a siderophore-quencher, and furanone C-30, a quorum sensing-inhibitor) together with four clinically relevant antibiotics (ciprofloxacin, colistin, meropenem, tobramycin) in 9×9 drug concentration matrices. We found that drug-interaction patterns were concentration dependent, with promising levels of synergies occurring at intermediate drug concentrations for certain drug pairs. We then tested whether antivirulence compounds are potent adjuvants, especially when treating antibiotic resistant clones. We found that the addition of antivirulence compounds to antibiotics could restore growth inhibition for most antibiotic resistant clones, and even abrogate or reverse selection for resistance in five drug combination cases. Molecular analyses suggest that selection against resistant clones occurs when resistance mechanisms involve restoration of protein synthesis, but not when efflux pumps are upregulated. Altogether, our work provides a first systematic analysis of antivirulence-antibiotic combinatorial treatments and suggests that such combinations have a high potential to be both effective in treating infections and in limiting the spread of antibiotic resistance.

scholarly journals Modeling the effect of vaccination on selection for antibiotic resistance in Streptococcus pneumoniae

2021 ◽  
Vol 13 (606) ◽  
pp. eaaz8690
Author(s):  
Nicholas G. Davies ◽  
Stefan Flasche ◽  
Mark Jit ◽  
Katherine E. Atkins
Keyword(s):  
Antibiotic Resistance ◽  
Streptococcus Pneumoniae ◽  
Bacterial Pathogens ◽  
Pneumococcal Vaccination ◽  
Pathogen Transmission ◽  
Drug Resistant ◽  
Bacterial Strains ◽  
Antibiotic Resistant ◽  
Selection For ◽  
The Impact

Vaccines against bacterial pathogens can protect recipients from becoming infected with potentially antibiotic-resistant pathogens. However, by altering the selective balance between antibiotic-sensitive and antibiotic-resistant bacterial strains, vaccines may also suppress—or spread—antibiotic resistance among unvaccinated individuals. Predicting the outcome of vaccination requires knowing what drives selection for drug-resistant bacterial pathogens and what maintains the circulation of both antibiotic-sensitive and antibiotic-resistant strains of bacteria. To address this question, we used mathematical modeling and data from 2007 on penicillin consumption and penicillin nonsusceptibility in Streptococcus pneumoniae (pneumococcus) invasive isolates from 27 European countries. We show that the frequency of penicillin resistance in S. pneumoniae can be explained by between-host diversity in antibiotic use, heritable diversity in pneumococcal carriage duration, or frequency-dependent selection brought about by within-host competition between antibiotic-resistant and antibiotic-sensitive S. pneumoniae strains. We used our calibrated models to predict the impact of non–serotype-specific pneumococcal vaccination upon the prevalence of S. pneumoniae carriage, incidence of disease, and frequency of S. pneumoniae antibiotic resistance. We found that the relative strength and directionality of competition between drug-resistant and drug-sensitive pneumococcal strains was the most important determinant of whether vaccination would promote, inhibit, or have little effect upon the evolution of antibiotic resistance. Last, we show that country-specific differences in pathogen transmission substantially altered the predicted impact of vaccination, highlighting that policies for managing antibiotic resistance with vaccines must be tailored to a specific pathogen and setting.

scholarly journals Inter and intra species social exploitation of antimicrobial resistance alters antibiotic efficacy

2020 ◽  
Vol 2 (7A) ◽  
Author(s):  
Michael Bottery ◽  
Ville Friman
Keyword(s):  
Antibiotic Resistance ◽  
Antimicrobial Resistance ◽  
Single Species ◽  
Multi Drug Resistance ◽  
Dependent Manner ◽  
Resistance Evolution ◽  
Selection Dynamics ◽  
Low Concentrations ◽  
Global Spread ◽  
Antibiotic Efficacy

The widespread use and misuse of antibiotics has led to the global spread of antimicrobial resistance. It is increasingly evident that very low concentrations of antibiotics, well below the MIC of sensitive strains, can select for antimicrobial resistance. However, it is less clear how social interactions within bacterial communities can alter sub-MIC selection dynamics, potentially confounding the outcomes of antibiotic treatments. Here we explore how antimicrobial resistances that inactivate antibiotics can be socially exploited by sensitive members of the microbial community at the inter and intra species level. We first show that a beta-lactamase encoded multi-drug resistance plasmid provides high levels of protection to plasmid-free antibiotic-sensitive cells within single-species populations in a frequency-dependent manner. Second, a similar protection can also occur between different species during polymicrobial infections. Using model Cystic Fibrosis lung communities, we demonstrate that the focal pathogen Pseudomonas aeruginosa can socially exploit antibiotic resistance in the presence of Stenotrophomonas maltophilia bacterium that can hydrolyse imipenem antibiotic. In contrast, the presence of Staphylococcus aureus, another commonly co-occurring CF pathogen, provided P. aeruginosa with no protection, but instead, made P. aeruginosa more susceptible to antibiotic due to intensified competition. These findings reveal that social exploitation of pre-occurring antimicrobial resistance, and inter-specific competition, can have a large effect on the efficacy of antibiotic treatments, highlighting the importance of microbial ecology for understanding antibiotic resistance evolution.

scholarly journals Antibiotic Resistance Increases Evolvability and Maximizes Opportunities Across Fitness Landscapes

2019 ◽  
Author(s):  
Fabrizio Spagnolo ◽  
Daniel E. Dykhuizen
Keyword(s):  
Public Health ◽  
Antibiotic Resistance ◽  
Public Health Problem ◽  
Fitness Landscapes ◽  
Resistant Bacteria ◽  
Major Question ◽  
Antibiotic Resistant ◽  
Resistant Strains ◽  
Compensatory Mutations ◽  
Selection For

AbstractAntibiotic resistance continues to grow as a public health problem. One of the reasons for this continued growth is that resistance to antibiotics is strongly selected for in the presence of antibiotics and weakly selected against after their removal. This is frequently thought to be due to the effects of compensatory mutations. However, compensatory mutations are often not found in clinically relevant strains of antibiotic resistant pathogens. Here, we conduct experiments in vitro that highlight the role that fine scale differences in environment play in the maintenance of populations after selection for resistance. We show that differences in the mode of growth, dictated by environmental factors, are capable of reliably changing the force and direction of selection. Our results show that antibiotic resistance can increase evolvability in environments if conditions for selection exist, selecting differentially for newly arising variation and moving populations to previously unavailable adaptive peaks.SignificanceAntibiotic resistant bacteria are a large and growing problem for public health. A major question has been why antibiotic resistant strains do not disappear when they must compete with higher fitness drug sensitive strains. Here we show that selection for antibiotic resistant strains is particularly sensitive to differences in environmental conditions and that these differences help to define the fitness landscapes upon which these populations adapt. The result is an increase in evolvability, with many adaptive peaks that drug resistant populations can explore through natural selection, making predictions of evolution difficult and selection against resistant strains improbable.

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