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Şimşek^, et al.,
Nature Communications (2025)
Spatial proximity dictates bacterial competition and expansion in microbial communities
In microbial communities, bacteria can inhibit or facilitate each other by altering their shared environment. Most studies of these interactions have focused on well-mixed environments, leaving spatial effects underexplored. Here, we show that in an antibiotic-treated community, bacterial spread depends on a facilitation mechanism that only emerges in spatial settings. The facilitating species enables the community’s range expansion but is then suppressed to a minority, making it a hidden initiator of the expansion. Focusing on two pathogens, immotile Klebsiella pneumoniae and motile Pseudomonas aeruginosa, we found that both tolerate a β-lactam antibiotic, with Pseudomonas being more resilient and dominating in well-mixed cultures. During range expansion, however, the antibiotic inhibits Pseudomonas' ability to spread unless it is near Klebsiella—which creates a ‘clear zone’ by degrading the antibiotic, at the expense of its own growth. As Pseudomonas spreads, it competitively suppresses Klebsiella. Our modeling and experimental analyses reveal that this facilitation operates at a millimeter scale. We also observed similar facilitation by a Bacillus species isolated from a hospital sink, in both pairwise and eight-member bacterial communities with its co-isolates. These findings suggest that spatially explicit experiments are essential to understand certain facilitation mechanisms and have implications for surface-associated microbial communities like biofilms and for polymicrobial infections involving drug-degrading immotile and drug-tolerant motile bacteria.
Şimşek, et al.,
Molecular Systems Biology (2024)
(also see an insightful commentary by Prof. Kyle R. Allison)
Combining mathematical modeling with quantitative experiments, we investigate spatial population dynamics and resistance evolution of a bacterial community under antibiotic stress with two competing interactions at different length-scales: local collective survival and global resource competition.
We found that
Global resource competition and local “collective survival” lead to heterogeneous growth and development of bacterial colonies (or patchiness).
Under intermediate antibiotic treatment, only a subset of colonies (the “rich”) with a sufficiently large initial seeding density survives.
Surviving colonies benefit from the global pool of resource and grow larger (or get “richer”) than when all colonies survive (in the absence of an antibiotic).
Local collective survival promotes the development of de novo mutants with enhanced antibiotic resistance.
(The wet-lab experiments started with laboratory Escherichia coli with engineered collective survival and then extended to the opportunistic human pathogen Pseudomonas aeruginosa)
Luo*, Lu*, Şimşek*, et al.,
Nature Microbiology (2024)
The collapse of cooperation during range expansion of Pseudomonas aeruginosa
It would not be unfair to say that all organisms cooperate for growth or survival, when needed. But virtually all populations also lend examples of cheaters- those that benefit from the cooperative behavior without contributing to it. Spatial structure is generally assumed to promote the evolutionary stability of cooperation, through clustering the cooperating individuals together so that cheaters cannot take the advantage of them. Oppositely, here we show that spatial structure can also underpin the collapse of cooperation in an expanding microbial population, when the expansion initially mandates cooperation. This cooperation is activated when nutrient levels are not too high but not too low either, at the expense of the cooperating individual's own growth. This expansion in a spatially structured environment allows a prolonged activation of cooperation making it vulnerable to cheating. Furthermore, we demonstrate and characterize divergent evolutionary outcomes of the expansion trait depending on the nutrient levels.
Şimşek, et al.,
Trends in Biotechnology, (2023)
Toward predictive engineering of gene circuits
In this invited Opinion article, we define what predictive engineering of gene circuits is. We dissect biological and environmental complexity into circuit and context complexities as confounding factors on the predictability in circuit engineering. We argue that predictive engineering of gene circuits is good for biotechnological applications such as target-specific drug delivery, metabolic engineering, microbiome engineering, and biomaterial synthesis. We argue that mechanistic modeling is useful to validate the predictability of an engineered gene circuit. We elaborate how machine learning can complement mechanistic modeling.
Şimşek*, Dawson*, et al.,
The International Society for Microbial Ecology (ISME) Journal, (2022)
Spatial regulation of cell motility and its fitness effect in a surface-attached bacterial community
Partial migration is an ecological phenomenon widely known for animal populations in which only a subset of the individuals is motile while others are sessile. Here, we investigate partial migration in an example from surface attached bacteria (Proteus mirabilis). We show that a growing colony becomes partially migratory by generating motile individuals preferentially at the outer region (green). We provide evidence that the suppression of the motile phenotype in the central regions is triggered by nutrient depletion and uncovered a signaling mechanism (Rcs) through which this regulation occurs. Finally, we show that this partial migration strategy facilitates prolonged starvation survival.
Şimşek and Kim, Proceedings of the National Academy of Sciences of the United States of America (PNAS), (2019)
Power-law tail in lag time distribution underlies bacterial persistence
Evading an antibiotic treatment by transiently non-growing is called bacterial persistence. This phenomenon reflects to bacterial population time-kill curves as a long-tail or virtually a plateau at long times. Previous single-cell studies observed persister cells. Past population-level measurements suggested a double-exponential dynamics for the time-kill curves with a slow phase describing the death kinetics of persisters preceded by a fast phase representing the death of other normal cells. In this study, by measuring the time length of no-growth (lag time) for ~13 000 single cells with microscopic observations, we unveil that the slow phase is actually not quite exponential, but rather is more close to a power-law decay. By mathematical arguments we show that such a power-law decay can emerge from many simultaneous random (Poisson) processes. Notably, this interpretation can embrace practically an infinite number of underlying molecular mechanisms. This is consistent with an already myriad mechanisms of persistence that have been reported to date.
Şimşek and Kim,
The International Society for Microbial Ecology (ISME) Journal, (2018)
The emergence of metabolic heterogeneity in isogenic bacterial cells
Starvation is not an exception, but the rule for microbial systems in nature. Nutrients only occasionally come and don' t last long. Thus, how-well microbes survive starvation and utilize the nutrients once available are fundamental determinants of their populations dynamics. Here, under the microscope in the laboratory, we unveil that carbon starved bacteria can promptly take up and catabolize a newly introduced carbon source (glucose). But a small fraction of an isogenic population emerges with inactive anabolism, while the majority exhibits anabolism rapidly and grows. The cells in this subpopulation with the partial metabolism can spontaneously activate anabolism and grow at later times (hours to days). Finally, we show evidence to suggest that the partial metabolism is promoted by oxidative stress, a presumably inevitable consequence of bacterial respiration under starvation.
* equal contribution
Bold indicates my first-authorship.
^ corresponding author
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