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"Johnson, David R."
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Wastewater treatment plant resistomes are shaped by bacterial composition, genetic exchange, and upregulated expression in the effluent microbiomes
Wastewater treatment plants (WWTPs) are implicated as hotspots for the dissemination of antibacterial resistance into the environment. However, the in situ processes governing removal, persistence, and evolution of resistance genes during wastewater treatment remain poorly understood. Here, we used quantitative metagenomic and metatranscriptomic approaches to achieve a broad-spectrum view of the flow and expression of genes related to antibacterial resistance to over 20 classes of antibiotics, 65 biocides, and 22 metals. All compartments of 12 WWTPs share persistent resistance genes with detectable transcriptional activities that were comparatively higher in the secondary effluent, where mobility genes also show higher relative abundance and expression ratios. The richness and abundance of resistance genes vary greatly across metagenomes from different treatment compartments, and their relative and absolute abundances correlate with bacterial community composition and biomass concentration. No strong drivers of resistome composition could be identified among the chemical stressors analyzed, although the sub-inhibitory concentration (hundreds of ng/L) of macrolide antibiotics in wastewater correlates with macrolide and vancomycin resistance genes. Contig-based analysis shows considerable co-localization between resistance and mobility genes and implies a history of substantial horizontal resistance transfer involving human bacterial pathogens. Based on these findings, we propose future inclusion of mobility incidence (M%) and host pathogenicity of antibiotic resistance genes in their quantitative health risk ranking models with an ultimate goal to assess the biological significance of wastewater resistomes with regard to disease control in humans or domestic livestock.
Journal Article
Timing of antibiotic administration determines the spread of plasmid-encoded antibiotic resistance during microbial range expansion
Plasmids are the main vector by which antibiotic resistance is transferred between bacterial cells within surface-associated communities. In this study, we ask whether there is an optimal time to administer antibiotics to minimize plasmid spread in new bacterial genotypes during community expansion across surfaces. We address this question using consortia of
Pseudomonas stutzeri
strains, where one is an antibiotic resistance-encoding plasmid donor and the other a potential recipient. We allowed the strains to co-expand across a surface and administered antibiotics at different times. We find that plasmid transfer and transconjugant proliferation have unimodal relationships with the timing of antibiotic administration, where they reach maxima at intermediate times. These unimodal relationships result from the interplay between the probabilities of plasmid transfer and loss. Our study provides mechanistic insights into the transfer and proliferation of antibiotic resistance-encoding plasmids within microbial communities and identifies the timing of antibiotic administration as an important determinant.
Plasmids are the main vector by which antibiotic resistance is transferred between bacterial cells within surface-associated communities. Here, Ma et al. show that plasmid spread peaks at intermediate antibiotic administration times, when the intermixing of plasmid donors and potential recipients is maximal.
Journal Article
Phage predation accelerates the spread of plasmid-encoded antibiotic resistance
Phage predation is generally assumed to reduce microbial proliferation while not contributing to the spread of antibiotic resistance. However, this assumption does not consider the effect of phage predation on the spatial organization of different microbial populations. Here, we show that phage predation can increase the spread of plasmid-encoded antibiotic resistance during surface-associated microbial growth by reshaping spatial organization. Using two strains of the bacterium
Escherichia coli
, we demonstrate that phage predation slows the spatial segregation of the strains during growth. This increases the number of cell-cell contacts and the extent of conjugation-mediated plasmid transfer between them. The underlying mechanism is that phage predation shifts the location of fastest growth from the biomass periphery to the interior where cells are densely packed and aligned closer to parallel with each other. This creates straighter interfaces between the strains that are less likely to merge together during growth, consequently slowing the spatial segregation of the strains and enhancing plasmid transfer between them. Our results have implications for the design and application of phage therapy and reveal a mechanism for how microbial functions that are deleterious to human and environmental health can proliferate in the absence of positive selection.
The impact of phage predation on spreading antimicrobial resistance is unclear in the context of its effects on microbial community spatial organization. Here, the authors show that phage predation can promote the spread of plasmid-encoded antibiotic resistance by increasing microbial spatial intermixing.
Journal Article
Engineering microbial consortia for controllable outputs
Much research has been invested into engineering microorganisms to perform desired biotransformations; nonetheless, these efforts frequently fall short of expected results due to the unforeseen effects of biofeedback regulation and functional incompatibility. In nature, metabolic function is compartmentalized into diverse organisms assembled into robust consortia, in which the division of labor is thought to lead to increased community efficiency and productivity. Here we consider whether and how consortia can be designed to perform bioprocesses of interest beyond the metabolic flexibility limitations of a single organism. Advances in post-genomic analysis of microbial consortia and application of high-resolution global measurements now offer the promise of systems-level understanding of how microbial consortia adapt to changes in environmental variables and inputs of carbon and energy. We argue that, when combined with appropriate modeling frameworks, systems-level knowledge can markedly improve our ability to predict the fate and functioning of consortia. Here we articulate our collective perspective on the current and future state of microbial community engineering and control while placing specific emphasis on ecological principles that promote control over community function and emergent properties.
Journal Article
Phage-mediated peripheral kill-the-winner facilitates the maintenance of costly antibiotic resistance
The persistence of antibiotic resistant (AR) bacteria in the absence of antibiotic pressure raises a paradox regarding the fitness costs associated with antibiotic resistance. These fitness costs should slow the growth of AR bacteria and cause them to be displaced by faster-growing antibiotic sensitive (AS) counterparts. Yet, even in the absence of antibiotic pressure, slower-growing AR bacteria can persist for prolonged periods of time. Here, we demonstrate a mechanism that can explain this apparent paradox. We hypothesize that lytic phage can modulate bacterial spatial organization to facilitate the persistence of slower-growing AR bacteria. Using surface-associated growth experiments with the bacterium
Escherichia coli
in conjunction with individual-based computational simulations, we show that phage disproportionately lyse the faster-growing AS counterpart cells located at the biomass periphery via a peripheral kill-the-winner dynamic. This enables the slower-growing AR cells to persist even when they are susceptible to the same phage. This phage-mediated selection is accompanied by enhanced bacterial diversity, further emphasizing the role of phage in shaping the assembly and evolution of bacterial systems. The mechanism is potentially relevant for any antibiotic resistance genetic determinant and has tangible implications for the management of bacterial populations via phage therapy.
In this work, authors report a mechanism for how phage can promote the spread of costly antibiotic resistance. They show that faster-growing sensitive cells dominate the biomass periphery where they encounter more phage, allowing for slower growing resistant cells to persist.
Journal Article
Rare and localized events stabilize microbial community composition and patterns of spatial self-organization in a fluctuating environment
Spatial self-organization is a hallmark of surface-associated microbial communities that is governed by local environmental conditions and further modified by interspecific interactions. Here, we hypothesize that spatial patterns of microbial cell-types can stabilize the composition of cross-feeding microbial communities under fluctuating environmental conditions. We tested this hypothesis by studying the growth and spatial self-organization of microbial co-cultures consisting of two metabolically interacting strains of the bacterium
Pseudomonas stutzeri
. We inoculated the co-cultures onto agar surfaces and allowed them to expand (i.e. range expansion) while fluctuating environmental conditions that alter the dependency between the two strains. We alternated between anoxic conditions that induce a mutualistic interaction and oxic conditions that induce a competitive interaction. We observed co-occurrence of both strains in rare and highly localized clusters (referred to as “spatial jackpot events”) that persist during environmental fluctuations. To resolve the underlying mechanisms for the emergence of spatial jackpot events, we used a mechanistic agent-based mathematical model that resolves growth and dispersal at the scale relevant to individual cells. While co-culture composition varied with the strength of the mutualistic interaction and across environmental fluctuations, the model provides insights into the formation of spatially resolved substrate landscapes with localized niches that support the co-occurrence of the two strains and secure co-culture function. This study highlights that in addition to spatial patterns that emerge in response to environmental fluctuations, localized spatial jackpot events ensure persistence of strains across dynamic conditions.
Journal Article
Successive range expansion promotes diversity and accelerates evolution in spatially structured microbial populations
Successive range expansions occur within all domains of life, where one population expands first (primary expansion) and one or more secondary populations then follow (secondary expansion). In general, genetic drift reduces diversity during range expansion. However, it is not clear whether the same effect applies during successive range expansion, mainly because the secondary population must expand into space occupied by the primary population. Here we used an experimental microbial model system to show that, in contrast to primary range expansion, successive range expansion promotes local population diversity. Because of mechanical constraints imposed by the presence of the primary population, the secondary population forms fractal-like dendritic structures. This divides the advancing secondary population into many small sub-populations and promotes intermixing between the primary and secondary populations. We further developed a mathematical model to simulate the formation of dendritic structures in the secondary population during succession. By introducing mutations in the primary or dendritic secondary populations, we found that mutations are more likely to accumulate in the dendritic secondary populations. Our results thus show that successive range expansion can promote intermixing over the short term and increase genetic diversity over the long term. Our results therefore have potentially important implications for predicting the ecological processes and evolutionary trajectories of microbial communities.
Journal Article
Evaluating critical and essential service access vulnerabilities
Access to critical and essential services (CES) is vital for community resilience, particularly in coastal areas facing natural hazards. We developed a novel transportation network analysis framework to assess access fragility (in terms of losing access), criticality (in terms of the importance of CES facilities), and equity of CES access across five Louisiana communities. We used drive time to the closest facility, marginal drive time to the second closest facility, and the number of alternatives within critical time thresholds as three measures for fragility analysis. Our findings show that fragility is not limited to rural areas—urban communities experiencing in-migration also face risks due to limited alternatives. Removing one facility at a time revealed that it can cause up to a 500% increase in drive times to dialysis centers and hospitals for residents of Morgan City and Stephensville, while, on average, removing one random high school results in a 6%–30% increase in drive time across communities. We also introduced a criticality ranking method using total population, percentage of the population without an alternative, and marginal drive time for populations without alternatives, and calculated rank stability across different weightings of these three measures to identify facilities that are consistently most critical. Cameron Parish had the highest concentration of critical facilities, though facilities in Slidell and Mandeville also ranked highly, highlighting potential capacity concerns for two communities with growing populations. Finally, our equity analysis, performed using Monte Carlo simulations, shows that Native populations are disproportionately affected by limited access to services (∼29% are identified as outliers for dialysis and hospital access), while White populations experience the lowest average drive times to most CES facilities.
Journal Article
Metabolite toxicity slows local diversity loss during expansion of a microbial cross-feeding community
Metabolic interactions between populations can influence patterns of spatial organization and diversity within microbial communities. Cross-feeding is one type of metabolic interaction that is pervasive within microbial communities, where one genotype consumes a resource into a metabolite while another genotype then consumes the metabolite. A typical feature of cross-feeding is that the metabolite may impose toxicity if it accumulates to sufficient concentrations. However, little is known about the effect of metabolite toxicity on spatial organization and local diversity within microbial communities. We addressed this knowledge gap by experimentally varying the toxicity of a single cross-fed metabolite and measuring the consequences on a synthetic microbial cross-feeding community. Our results demonstrate that metabolite toxicity slows demixing and thus slows local diversity loss of the metabolite-producing population. Using mathematical modeling, we show that this is because toxicity slows growth, which enables more cells to emigrate from the founding region and contribute towards population expansion. Our results show that metabolite toxicity is an important factor affecting local diversity within microbial communities and that spatial organization can be affected by non-intuitive mechanisms.
Journal Article