Low Levels of β-Lactam Antibiotics Induce Extracellular DNA Release and Biofilm Formation in Staphylococcus aureus

Kaplan, Jeffrey B.; Izano, Era A.; Gopal, Prerna; Karwacki, Michael T.; Kim, Sangho; Bose, Jeffrey L.; Bayles, Kenneth W.; Horswill, Alexander R.

doi:10.1128/mbio.00198-12

Cited by 248 publications

(264 citation statements)

References 41 publications

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“…Biofilm formation is a common stress response in many bacteria (55), and we hypothesized that a similar response was occurring in A. actinomycetemcomitans when exposed to erythromycin. A few factors that mediate antibiotic-induced attachment have been characterized (56,57). However, to our knowledge such factors have not been explored systematically.…”

Section: Resultsmentioning

confidence: 99%

“…This clinically relevant behavior could prime A. actinomycetemcomitans for higher, more lethal antibiotic concentrations during infection. In other bacteria, similar phenomena are mediated by cyclic di-GMP signaling (56) and extracellular DNA release (57). To discover factors that mediate this process in A. actinomycetemcomitans, we developed a novel Tn-seq-based screen (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Defining Genetic Fitness Determinants and Creating Genomic Resources for an Oral Pathogen

Narayanan

Ramsey

Stacy

et al. 2017

Appl Environ Microbiol

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Periodontitis is a microbial infection that destroys the structures that support the teeth. Although it is typically a chronic condition, rapidly progressing, aggressive forms are associated with the oral pathogen Aggregatibacter actinomycetemcomitans. One of this bacterium's key virulence traits is its ability to attach to surfaces and form robust biofilms that resist killing by the host and antibiotics. Though much has been learned about A. actinomycetemcomitans since its initial discovery, we lack insight into a fundamental aspect of its basic biology, as we do not know the full set of genes that it requires for viability (the essential genome). Furthermore, research on A. actinomycetemcomitans is hampered by the field's lack of a mutant collection. To address these gaps, we used rapid transposon mutant sequencing (Tn-seq) to define the essential genomes of two strains of A. actinomycetemcomitans, revealing a core set of 319 genes. We then generated an arrayed mutant library comprising Ͼ1,500 unique insertions and used a sequencing-based approach to define each mutant's position (well and plate) in the library. To demonstrate its utility, we screened the library for mutants with weakened resistance to subinhibitory erythromycin, revealing the multidrug efflux pump AcrAB as a critical resistance factor. During the screen, we discovered that erythromycin induces A. actinomycetemcomitans to form biofilms. We therefore devised a novel Tnseq-based screen to identify specific factors that mediate this phenotype and in follow-up experiments confirmed 4 mutants. Together, these studies present new insights and resources for investigating the basic biology and disease mechanisms of a human pathogen. IMPORTANCE Millions suffer from gum disease, which often is caused by Aggregatibacter actinomycetemcomitans, a bacterium that forms antibiotic-resistant biofilms. To fully understand any organism, we should be able to answer: what genes does it require for life? Here, we address this question for A. actinomycetemcomitans by determining the genes in its genome that cannot be mutated. As for the genes that can be mutated, we archived these mutants into a library, which we used to find genes that contribute to antibiotic resistance, leading us to discover that antibiotics cause A. actinomycetemcomitans to form biofilms. We then devised an approach to find genes that mediate this process and confirmed 4 genes. These results illuminate new fundamental traits of a human pathogen.KEYWORDS Aggregatibacter, Tn-seq, antibiotics, biofilms, essential genome O ne of the longest-studied human microbiomes is the "animalcules" (bacteria), first observed by van Leeuwenhoek (1), that inhabit the oral cavity. Oral bacteria readily attach to tooth surfaces and develop into spatially organized, multispecies biofilms (2). These communities also persist beneath the gum line in the subgingival pocket, where they are kept in check by host immune cells (3). Though normally benign, subgingival communities can accumulate opportunistic oral p...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Defining Genetic Fitness Determinants and Creating Genomic Resources for an Oral Pathogen

Narayanan

Ramsey

Stacy

et al. 2017

Appl Environ Microbiol

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“…Cooperation can be affected by stress directly through differential selection on cooperative phenotypes (14,15), or by inducing specific plastic behaviors (16)(17)(18)(19)(20)(21)(22), especially when cooperation leads to increased stress resistance. However, in the absence of a direct benefit of the cooperative behavior against stress, the ecological and evolutionary outcomes of the interactions between nondefensive public goods and stress responses are less clear and are potentially complex.…”

mentioning

confidence: 99%

Antibiotic stress selects against cooperation in the pathogenic bacterium Pseudomonas aeruginosa

Vasse

Noble

Akhmetzhanov

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Cheats are a pervasive threat to public goods production in natural and human communities, as they benefit from the commons without contributing to it. Although ecological antagonisms such as predation, parasitism, competition, and abiotic environmental stress play key roles in shaping population biology, it is unknown how such stresses generally affect the ability of cheats to undermine cooperation. We used theory and experiments to address this question in the pathogenic bacterium, Pseudomonas aeruginosa. Although public goods producers were selected against in all populations, our competition experiments showed that antibiotics significantly increased the advantage of nonproducers. Moreover, the dominance of nonproducers in mixed cultures was associated with higher resistance to antibiotics than in either monoculture. Mathematical modeling indicates that accentuated costs to producer phenotypes underlie the observed patterns. Mathematical analysis further shows how these patterns should generalize to other taxa with public goods behaviors. Our findings suggest that explaining the maintenance of cooperative public goods behaviors in certain natural systems will be more challenging than previously thought. Our results also have specific implications for the control of pathogenic bacteria using antibiotics and for understanding natural bacterial ecosystems, where subinhibitory concentrations of antimicrobials frequently occur.evolution | cooperation | antibiotics | social behavior | resistance P ublic goods production is a characteristic of a diverse range of taxa, from microbes to humans (1-3). Explaining the persistence of this costly behavior is challenging, because cheats can exploit the commons without contributing. Kin selection theory has proven to be a successful framework for addressing this question, with the central prediction that cooperation is favored by sufficient benefits to, and positive assortment between, cooperators (4-8). For example, recent study in experimental bacterial populations has elucidated mechanisms such as assortment emerging from limited or budding dispersal (9, 10) and kin discrimination (11, 12) that are consistent with kin selection fostering cooperative behaviors (e.g., refs. 8 and 13). However, despite this accumulating consensus, little is known about how social populations respond to differences and variation in abiotic and biotic components of their environment. In particular, it is unclear how ecological antagonisms affect the ability of cheats to invade cooperator communities.Cooperation can be affected by stress directly through differential selection on cooperative phenotypes (14, 15), or by inducing specific plastic behaviors (16-22), especially when cooperation leads to increased stress resistance. However, in the absence of a direct benefit of the cooperative behavior against stress, the ecological and evolutionary outcomes of the interactions between nondefensive public goods and stress responses are less clear and are potentially complex. Cooperation may be infl...

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“…Later, more research papers discussed the phenomenon that low-level antibiotics induce the formation of biofilms. For instance, Kaplan et al [76] discovered that the low levels of β-lactam antibiotics-including methicillin, ampicillin, amoxicillin, and cloxacillin-would induce the formation of biofilms by various Staphylococcus aureus strains, a well-known human pathogen. The biomass in the induced biofilms was 10 times higher than those without the exposure of antibiotics.…”

Section: The Inducing Effects Of Sublethal Levels Of Stressors On Biomentioning

confidence: 99%

Modeling Biofilms in Water Systems with New Variables: A Review

Xia

Tao

et al. 2017

Water

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Abstract:In nature, microorganisms mainly live in biofilms rather than planktonically to defend against various environmental stimuli. Understanding and predicting the dynamics and mechanisms of biofilms is of grand importance to human life. Besides experimental approaches, modeling provides a powerful tool to describe biofilms mathematically, and the in silico simulation offers a deep insight into the underlying functional machineries of biofilms. In this review, we briefly summarized the main advances in biofilm modeling, including the 1D model, multidimensional model, as well as the incorporation of extracellular polymeric substance and quorum sensing signals. Specifically, we focus on recent experimental advances in biofilms, which may challenge the current modeling systems via newly discovered properties and novel participants in natural water systems. We hope this article could build a bridge between in silico modeling and new experimental discoveries, and, in particular, we wish to attract more attention to biofilm-related-environmental issues at various scales.

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Low Levels of β-Lactam Antibiotics Induce Extracellular DNA Release and Biofilm Formation in Staphylococcus aureus

Cited by 248 publications

References 41 publications

Defining Genetic Fitness Determinants and Creating Genomic Resources for an Oral Pathogen

Defining Genetic Fitness Determinants and Creating Genomic Resources for an Oral Pathogen

Antibiotic stress selects against cooperation in the pathogenic bacterium Pseudomonas aeruginosa

Modeling Biofilms in Water Systems with New Variables: A Review

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