Antibiotic-Mediated Selection of Quorum-Sensing-Negative Staphylococcus aureus

Paulander, Wilhelm; Varming, Anders K.; Bæk, Kristoffer T.; Haaber, Jakob; Frees, Dorte; Ingmer, Hanne

doi:10.1128/mbio.00459-12

Cited by 57 publications

(67 citation statements)

References 53 publications

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“…1 and 2) (27). Although some previous studies are consistent with QS being a cooperative social trait, they have not shown the fitness benefit of responding to signal at the group level (5,40). Consequently, they are also consistent with a fitness benefit due to a nonsocial trait.…”

Section: Discussionsupporting

confidence: 65%

“…For example, if QS is a social trait, then this could explain the potentially contradictory results that agr mutants are less virulent in clonal infections of animal models (lower cooperation) but are still able to spread in infections of humans ("cheats" [see below] can exploit cooperators) (1-4). This is important because direct fitness, and not social, explanations have been invoked for the occurrence of agr mutants, based on the metabolic cost of agr expression or the fact that agr mutants are better adapted to certain environments (2,5,6).…”

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confidence: 99%

“…S. aureus infections can be difficult to treat because of antibiotic-resistant strains, such as methicillin-resistant S. aureus (MRSA), which are resistant to beta-lactam antibiotics. Globally, MRSA infection rates are increasing (2,5,6).…”

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confidence: 99%

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Cooperation, Quorum Sensing, and Evolution of Virulence in Staphylococcus aureus

et al. 2014

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bThe virulence and fitness in vivo of the major human pathogen Staphylococcus aureus are associated with a cell-to-cell signaling mechanism known as quorum sensing (QS). QS coordinates the production of virulence factors via the production and sensing of autoinducing peptide (AIP) signal molecules by the agr locus. Here we show, in a wax moth larva virulence model, that (i) QS in S. aureus is a cooperative social trait that provides a benefit to the local population of cells, (ii) agr mutants, which do not produce or respond to QS signal, are able to exploit the benefits provided by the QS of others ("cheat"), allowing them to increase in frequency when in mixed populations with cooperators, (iii) these social interactions between cells determine virulence, with the host mortality rate being negatively correlated to the percentage of agr mutants ("cheats") in a population, and (iv) a higher within-host relatedness (lower strain diversity) selects for QS and hence higher virulence. Our results provide an explanation for why agr mutants show reduced virulence in animal models but can be isolated from infections of humans. More generally, by providing the first evidence that QS is a cooperative social behavior in a Gram-positive bacterium, our results suggest convergent, and potentially widespread, evolution for signaling to coordinate cooperation in bacteria. Staphylococcus aureus is a major human pathogen, responsible for 1% of all hospital admissions and leading to an estimated cost of $9.5 billion per year in the United States alone (1-4). Infections caused by S. aureus range from relatively mild boils and infected skin wounds to those with high mortality rates, such as bacteremia, infective endocarditis, and toxic shock. S. aureus infections can be difficult to treat because of antibiotic-resistant strains, such as methicillin-resistant S. aureus (MRSA), which are resistant to beta-lactam antibiotics. Globally, MRSA infection rates are increasing (2, 5, 6).The virulence and growth in vivo of S. aureus depend upon quorum sensing (QS) via the accessory gene regulator (agr) locus (1,7,8). Cells release a small autoinducing peptide (AIP), the accumulation of which induces the production and secretion of both more AIP and a range of virulence factors. These virulence factors include hemolysins ␣, ␤, ␦, and ␥, toxic shock syndrome toxin (TSST), enterotoxins, Panton-Valentine leukocidin (PVL), and exfoliatins A and B (8-10). At high cell densities, or when cells are enclosed in small spaces, the agr system leads to positive feedback in the production of AIP and a significant increase in the production of virulence factors (11-15).It is commonly assumed that QS is a cooperative social trait, in which the benefits of virulence factors are shared between the local population of cells and their production is coordinated across cells via QS (16, 17). However, there has been no empirical demonstration that QS in S. aureus, or any other Gram-positive bacteria, is a cooperative social trait (see Discussion). Evidence that QS...

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Section: Discussionsupporting

confidence: 65%

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confidence: 99%

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Cooperation, Quorum Sensing, and Evolution of Virulence in Staphylococcus aureus

et al. 2014

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“…The authors suggested that this effect occurs because the investment in cooperative secretions limits growth and thereby competitive ability. Alternatively, in some particular cases, antagonisms may directly increase the benefit to nonproducers by inducing the production of costly public goods (20,61). In Staphylococcus aureus, for example, sublethal doses of ciprofloxacin, mupirocin, or rifampicin induce the expression of the costly effector molecule regulating the quorum-sensing system agr, thereby favoring agr-negative variants (61).…”

Section: Discussionmentioning

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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“…Competitive fitness was assessed using methods outlined previously (39). Overnight cultures of S. aureus P0 or P10 were diluted 1:10 and adjusted to an OD 600 of 1.5.…”

Section: Chemicalmentioning

confidence: 99%

Altered Competitive Fitness, Antimicrobial Susceptibility, and Cellular Morphology in a Triclosan-Induced Small-Colony Variant of Staphylococcus aureus

Forbes

Latimer

Bazaid

et al. 2015

Antimicrob Agents Chemother

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Staphylococcus aureus can produce small-colony variants (SCVs) that express various phenotypes. While their significance is unclear, SCV propagation may be influenced by relative fitness, antimicrobial susceptibility, and the underlying mechanism. We have investigated triclosan-induced generation of SCVs in six S. aureus strains, including methicillin-resistant S. aureus (MRSA). Parent strains (P0) were repeatedly passaged on concentration gradients of triclosan using a solid-state exposure system to generate P10. P10 was subsequently passaged without triclosan to generate X10. Susceptibility to triclosan and 7 antibiotics was assessed at all stages. For S. aureus ATCC 6538, SCVs were further characterized by determining microbicide susceptibility and competitive fitness. Cellular morphology was examined using electron microscopy, and protein expression was evaluated through proteomics. Triclosan susceptibility in all SCVs (which could be generated from 4/6 strains) was markedly decreased, while antibiotic susceptibility was significantly increased in the majority of cases. An SCV of S. aureus ATCC 6538 exhibited significantly increased susceptibility to all tested microbicides. Cross-wall formation was impaired in this bacterium, while expression of FabI, a target of triclosan, and IsaA, a lytic transglycosylase involved in cell division, was increased. The P10 SCV was 49% less fit than P0. In summary, triclosan exposure of S. aureus produced SCVs in 4/6 test bacteria, with decreased triclosan susceptibility but with generally increased antibiotic susceptibility. An SCV derived from S. aureus ATCC 6538 showed reduced competitive fitness, potentially due to impaired cell division. In this SCV, increased FabI expression could account for reduced triclosan susceptibility, while IsaA may be upregulated in response to cell division defects. Staphylococcus aureus small-colony variants (SCVs) are characterized by low growth rate and the formation of small nonpigmented colonies (1, 2). They are commonly, but not exclusively, related to antibiotic exposure (3) and have been shown to display diverse phenotypic characteristics, including reduced beta-hemolysis, coagulase, and DNase activities (4), enhanced intracellular survival (5), impaired biofilm formation (6), reduced virulence (6), and low intrinsic susceptibility to certain antibiotics, cationic microbicides, and antimicrobial peptides (7,8). While all SCVs are not physiologically the same, certain SCVs have been reported to cause persistent skin, bone, and device-associated infections, and they have been isolated from patients undergoing prolonged antibiotic therapy (2, 9, 10). Due to their uncommon morphological features and pinpoint colony size, SCVs may be overlooked or misidentified in clinical microbiology laboratories, potentially confounding their identification.The phenotypic variation observed in S. aureus SCVs is often attributed to auxotrophy for menadione, hemin, or thiamine due to mutations in their respective genes. This results in impaired synthesis...

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Antibiotic-Mediated Selection of Quorum-Sensing-Negative Staphylococcus aureus

Cited by 57 publications

References 53 publications

Cooperation, Quorum Sensing, and Evolution of Virulence in Staphylococcus aureus

Cooperation, Quorum Sensing, and Evolution of Virulence in Staphylococcus aureus

Antibiotic stress selects against cooperation in the pathogenic bacterium Pseudomonas aeruginosa

Altered Competitive Fitness, Antimicrobial Susceptibility, and Cellular Morphology in a Triclosan-Induced Small-Colony Variant of Staphylococcus aureus

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