Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2011 Oct 11;2(5):e00131-11.
doi: 10.1128/mBio.00131-11. Print 2011.

The sociomicrobiology of antivirulence drug resistance: a proof of concept

Brett Mellbye  1 , Martin Schuster
Affiliations

The sociomicrobiology of antivirulence drug resistance: a proof of concept

Brett Mellbye et al. mBio. .

Abstract

Antivirulence drugs disarm rather than kill pathogens and are thought to alleviate the problem of resistance, although there is no evidence to support this notion. Quorum sensing (QS) often controls cooperative virulence factor production and is therefore an attractive antivirulence target, for which inhibitors (QSI) have been developed. We designed a proof-of-principle experiment to investigate the impact of bacterial social interactions on the evolution of QSI resistance. We cocultured Pseudomonas aeruginosa QS-deficient mutants with small proportions of the QS-proficient wild type, which in the absence of QSI mimic QSI-sensitive and -resistant variants, respectively. We employed two different QS-dependent nutrients that are degraded by extracellular (public) and cell-associated (private) enzymes. QS mutants (QSI-sensitive mimics) behaved as social cheaters that delayed population growth and prevented enrichment of wild-type cooperators (QSI-resistant mimics) only when nutrient acquisition was public, suggesting that QSI resistance would not spread. This highlights the potential for antivirulence strategies that target cooperative behaviors and provides a conceptual framework for future studies.

PubMed Disclaimer

Figures

FIG 1
FIG 1
The role of social conflict in the emergence of QSI resistance revealed through coculturing. Assays were performed with a P. aeruginosa lasR rhlR mutant (QSI-sensitive mimic, S) and its wild-type parent (QSI-resistant mimic, R). (A and B) Duration of culture growth to stationary phase in minimal medium with BSA (A) or adenosine (B) as the sole C source. The relative amounts of R and S inocula (normalized for between-culture comparison) as well as the percentages of R in the respective single cultures and cocultures are indicated. Arrows indicate that the culture failed to reach stationary phase within the duration of the experiment (15 days). Error bars indicate standard deviations of the means of four replicates. Statistically significant differences between pairs (R and S alone; R + S coculture and the corresponding R-only culture) were determined using one-way analysis of variance and Bonferroni’s post hoc multiple comparison. Brackets with asterisks indicate P values of <0.05. (C) Enrichment of the resistant mimic in coculture. Initial and final frequencies of R inoculated at approximately 1% (circles), 10% (triangles), and 50% (squares) in BSA and adenosine media (open and filled symbols, respectively) are shown. Error bars indicate standard deviations of the means of four replicates. Statistical significance was determined by a two-tailed unpaired t test. All changes in the mean R frequency were found to be significant (P < 0.05) except for the BSA coculture inoculated at 1%. (D) Relative fitness (v) of the resistant mimic in BSA (open circles) and adenosine (filled circles) cultures. Relative fitness was calculated as the comparison of the initial and final R frequencies. Differences in the mean relative fitness between BSA cultures inoculated at approximately 10% and 50% were not significant [F(1,6) = 0.151, P > 0.05], and differences in the mean relative fitness between all adenosine cultures were significant [F(2,9) = 11.5, P < 0.05], as determined by one-way analysis of variance.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Clatworthy AE, Pierson E, Hung DT. 2007. Targeting virulence: a new paradigm for antimicrobial therapy. Nat. Chem. Biol. 3:541–548 - PubMed
    1. Projan SJ, Shlaes DM. 2004. Antibacterial drug discovery: is it all downhill from here? Clin. Microbiol. Infect. 10(Suppl. 4):18–22 - PubMed
    1. Rasko DA, Sperandio V. 2010. Anti-virulence strategies to combat bacteria-mediated disease. Nat. Rev. Drug Discov. 9:117–128 - PubMed
    1. Waters CM, Bassler BL. 2005. Quorum sensing: cell-to-cell communication in bacteria. Annu. Rev. Cell Dev. Biol. 21:319–346 - PubMed
    1. Schuster M, Greenberg EP. 2006. A network of networks: quorum-sensing gene regulation in Pseudomonas aeruginosa. Int. J. Med. Microbiol. 296:73–81 - PubMed

Publication types

MeSH terms

LinkOut - more resources