Alex R. Hall

Last Name

Hall

First Name

Alex R.

ORCID

0000-0002-3654-1373

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09497 - Hall, Alex / Hall, Alex

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Publications 1 - 10 of 64

Multi-layered ecological interactions determine growth of clinical antibiotic-resistant strains within human microbiomes
Leon-Sampedro, Ricardo; Boumasmoud, Mathilde; Reichlin , Markus; et al. (2025)
Nature Communications
The spread of antibiotic-resistant bacteria in the gut depends on their ability to establish within complex microbial communities. However, the role of various ecological factors in modulating this process, particularly in the absence of antibiotic selection, remains poorly understood. We hypothesize that different strains within the same species vary in their ability to colonize due to distinct interactions with resident microbiota. Using human gut-microbiome samples in replicated anaerobic microcosms with and without antibiotics, we test multiple clinically relevant and phylogenetically distinct Escherichia coli strains carrying extended-spectrum beta-lactamase (ESBL) or carbapenemase plasmids. While antibiotics influence the growth of incoming resistant strains, some are successful even without antibiotics. Growth outcomes depend on a combination of intrinsic growth capacities in relevant abiotic conditions, competition with resident E. coli, and strain-specific shifts in resident community composition. We also detect horizontal transfer of resistance plasmids in some conditions, but transconjugants remain rare across treatments. Here, we show that the success of antibiotic-resistant bacteria depends on strain-specific ecological interactions, helping to explain the spread and persistence of resistance in human microbiomes.
Computational and in vitro evaluation of probiotic treatments for nasal Staphylococcus aureus decolonization
Tepekule, Burcu; Barcik, Weronika; Staiger, Willy I.; et al. (2025)
Proceedings of the National Academy of Sciences of the United States of America
Despite the rising challenge of antibiotic resistance, current approaches to eradicate nasal pathobionts Staphylococcus aureus and Streptococcus pneumoniae rely on antibacterials. An alternative is the artificial inoculation of commensal bacteria, i.e., probiotic treatment, supported by the increasing evidence for commensal-mediated inhibition of pathogens. To systematically investigate the potential of this approach, we developed a quantitative framework simulating the nasal microbiome dynamics by combining mathematical modeling with longitudinal microbiota data. By inferring community parameters using 16S ribosomal RNA (rRNA) amplicon sequencing data and simulating the nasal microbial dynamics of patients colonized with S. aureus, we compared the decolonization performance of probiotic and antibiotic treatments under different assumptions on patients’ community composition and susceptibility profile. To further compare the robustness of these treatments, we simulated an S. aureus challenge and quantified the recolonization probability. Through in vitro experiments using nasal swabs of adults colonized with S. aureus, we confirmed that after antibiotic treatment, recolonization of S. aureus was inhibited in samples treated with a probiotic mixture compared to the nontreated control. Our results suggest that probiotic treatment outperforms antibiotics in terms of decolonization performance, recolonization robustness, and leads to less collateral reduction in the microbiome diversity. Thus, probiotic treatment may provide a promising alternative to combat antibiotic resistance, with the additional advantage of personalized treatment options via using the patient’s own metagenomic data. The combination of an in silico framework with in vitro experiments using clinical samples reported in this work is an important step forward to further investigate this alternative in clinical trials.
The cost of antibiotic resistance depends on evolutionary history in Escherichia coli
Angst, Daniel C.; Hall, Alex R. (2013)
BMC Evolutionary Biology
Background The persistence of antibiotic resistance depends on the fitness effects of resistance elements in the absence of antibiotics. Recent work shows that the fitness effect of a given resistance mutation is influenced by other resistance mutations on the same genome. However, resistant bacteria acquire additional beneficial mutations during evolution in the absence of antibiotics that do not alter resistance directly but may modify the fitness effects of new resistance mutations. Results We experimentally evolved rifampicin-resistant and sensitive Escherichia coli in a drug-free environment, before measuring the effects of new resistance elements on fitness in antibiotic-free conditions. Streptomycin-resistance mutations had small fitness effects in rifampicin-resistant genotypes that had adapted to antibiotic-free growth medium, compared to the same genotypes without adaptation. We observed a similar effect when resistance was encoded by a different mechanism and carried on a plasmid. Antibiotic-sensitive bacteria that adapted to the same conditions showed the same pattern for some resistance elements but not others. Conclusions Epistatic variation of costs of resistance can result from evolution in the absence of antibiotics, as well as the presence of other resistance mutations.
Microbial community composition interacts with local abiotic conditions to drive colonization resistance in human gut microbiome samples
Baumgartner, Michael; Pfrunder Cardozo, Katia R.; Hall, Alex R. (2021)
Proceedings of the Royal Society B: Biological Sciences
Biological invasions can alter ecosystem stability and function, and predicting what happens when a new species or strain arrives remains a major challenge in ecology. In the mammalian gastrointestinal tract, susceptibility of the resident microbial community to invasion by pathogens has important implications for host health. However, at the community level, it is unclear whether susceptibility to invasion depends mostly on resident community composition (which microbes are present), or also on local abiotic conditions (such as nutrient status). Here, we used a gut microcosm system to disentangle some of the drivers of susceptibility to invasion in microbial communities sampled from humans. We found resident microbial communities inhibited an invading Escherichia coli strain, compared to community-free control treatments, sometimes excluding the invader completely (colonization resistance). These effects were stronger at later time points, when we also detected altered community composition and nutrient availability. By separating these two components (microbial community and abiotic environment), we found taxonomic composition played a crucial role in suppressing invasion, but this depended critically on local abiotic conditions (adapted communities were more suppressive in nutrient-depleted conditions). This helps predict when resident communities will be most susceptible to invasion, with implications for optimizing treatments based on microbiota management.
Epistasis buffers the fitness effects of rifampicin-resistance mutations in Pseudomonas aeruginosa
Hall, Alex R.; MacLean, R. Craig (2011)
Evolution
Human-associated microbiota suppress invading bacteria even under disruption by antibiotics
Letten, Andrew D.; Baumgartner, Michael; Pfrunder Cardozo, Katia R.; et al. (2021)
The ISME Journal
In light of their adverse impacts on resident microbial communities, it is widely predicted that broad-spectrum antibiotics can promote the spread of resistance by releasing resistant strains from competition with other strains and species. We investigated the competitive suppression of a resistant strain of Escherichia coli inoculated into human-associated communities in the presence and absence of the broad and narrow spectrum antibiotics rifampicin and polymyxin B, respectively. We found strong evidence of community-level suppression of the resistant strain in the absence of antibiotics and, despite large changes in community composition and abundance following rifampicin exposure, suppression of the invading resistant strain was maintained in both antibiotic treatments. Instead, the strength of competitive suppression was more strongly associated with the source community (stool sample from individual human donor). This suggests microbiome composition strongly influences the competitive suppression of antibiotic-resistant strains, but at least some antibiotic-associated disruption can be tolerated before competitive release is observed. A deeper understanding of this association will aid the development of ecologically-aware strategies for managing antibiotic resistance.
Resident microbial communities inhibit growth and antibiotic-resistance evolution of Escherichia coli in human gut microbiome samples
Baumgartner, Michael; Bayer, Florian; Pfrunder-Cardozo, Katia R.; et al. (2020)
PLoS Biology
Countering the rise of antibiotic-resistant pathogens requires improved understanding of how resistance emerges and spreads in individual species, which are often embedded in complex microbial communities such as the human gut microbiome. Interactions with other microorganisms in such communities might suppress growth and resistance evolution of individual species (e.g., via resource competition) but could also potentially accelerate resistance evolution via horizontal transfer of resistance genes. It remains unclear how these different effects balance out, partly because it is difficult to observe them directly. Here, we used a gut microcosm approach to quantify the effect of three human gut microbiome communities on growth and resistance evolution of a focal strain of Escherichia coli. We found the resident microbial communities not only suppressed growth and colonisation by focal E. coli but also prevented it from evolving antibiotic resistance upon exposure to a beta-lactam antibiotic. With samples from all three human donors, our focal E. coli strain only evolved antibiotic resistance in the absence of the resident microbial community, even though we found resistance genes, including a highly effective resistance plasmid, in resident microbial communities. We identified physical constraints on plasmid transfer that can explain why our focal strain failed to acquire some of these beneficial resistance genes, and we found some chromosomal resistance mutations were only beneficial in the absence of the resident microbiota. This suggests, depending on in situ gene transfer dynamics, interactions with resident microbiota can inhibit antibiotic-resistance evolution of individual species.
Reversing resistance: different routes and common themes across pathogens
Allen, Richard C.; Engelstädter, Jan; Bonhoeffer, Sebastian; et al. (2017)
Proceedings of the Royal Society B: Biological Sciences
Resistance spreads rapidly in pathogen or pest populations exposed to bio- cides, such as fungicides and antibiotics, and in many cases new biocides are in short supply. How can resistance be reversed in order to prolong the effec- tiveness of available treatments? Some key parameters affecting reversion of resistance are well known, such as the fitness cost of resistance. However, the population biological processes that actually cause resistance to persist or decline remain poorly characterized, and consequently our ability to manage reversion of resistance is limited. Where do susceptible genotypes that replace resistant lineages come from? What is the epidemiological scale of reversion? What information do we need to predict the mechanisms or likelihood of reversion? Here, we define some of the population biological processes that can drive reversion, using examples from a wide range of taxa and biocides. These processes differ primarily in the origin of revertant genotypes, but also in their sensitivity to factors such as coselection and compensatory evolution that can alter the rate of reversion, and the likelihood that resistance will re-emerge upon re-exposure to biocides. We therefore argue that discriminating among different types of reversion allows for better prediction of where resistance is most likely to persist.
Transition bias influences the evolution of antibiotic resistance in Mycobacterium tuberculosis
Payne, Joshua L.; Menardo, Fabrizio; Trauner, Andrej; et al. (2019)
PLoS Biology
Transition bias, an overabundance of transitions relative to transversions, has been widely reported among studies of the rates and spectra of spontaneous mutations. However, demonstrating the role of transition bias in adaptive evolution remains challenging. In particular, it is unclear whether such biases direct the evolution of bacterial pathogens adapting to treatment. We addressed this challenge by analyzing adaptive antibiotic-resistance mutations in the major human pathogen Mycobacterium tuberculosis (MTB). We found strong evidence for transition bias in two independently curated data sets comprising 152 and 208 antibiotic-resistance mutations. This was true at the level of mutational paths (distinct adaptive DNA sequence changes) and events (individual instances of the adaptive DNA sequence changes) and across different genes and gene promoters conferring resistance to a diversity of antibiotics. It was also true for mutations that do not code for amino acid changes (in gene promoters and the 16S ribosomal RNA gene rrs) and for mutations that are synonymous to each other and are therefore likely to have similar fitness effects, suggesting that transition bias can be caused by a bias in mutation supply. These results point to a central role for transition bias in determining which mutations drive adaptive antibiotic resistance evolution in a key pathogen.
Modification of Escherichia coli-bacteriophage interactions by surfactants and antibiotics in vitro
Scanlan, Pauline D.; Bischofberger, Anna M.; Hall, Alex R. (2017)
FEMS Microbiology Ecology
Although experiments indicate that the abiotic environment plays an important role in bacterial interactions with their parasitic viruses (bacteriophages or phages), it is not yet clear how exposure to compounds present in nature alters the impact of phages on bacterial growth and evolution. To address this question, we exposed Escherichia coli K12 MG1655, in combination with three lytic phages, to various substances that natural and clinical microbial populations are likely to encounter: bile salts (present in mammalian gastrointestinal tracts), sodium dodecyl sulfate (SDS, a common surfactant in cleaning and hygiene products) and four antibiotics (present at variable concentrations in natural and clinical environments). Our results show that bile salts and SDS can reduce the detrimental effect of phages on bacterial growth. In some cases these compounds completely mitigated any negative effects of phages on bacterial growth and consequently bacteria did not evolve resistance to phages in these conditions. The proportional effects of phages were unaffected by antibiotics in most combinations, excepting three cases of phage-drug synergy. These results suggest that accounting for interactions between phages and environmental factors such as surfactants and antibiotics will improve understanding of both bacterial growth and resistance evolution to phages in vivo and in nature.

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Alex R. Hall

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