Senescence can explain microbial persistence.

It has been known for many years that small fractions of persister cells resist killing in many bacterial colony-antimicrobial confrontations. These persisters are not believed to be mutants. Rather it has been hypothesized that they are phenotypic variants. Current models allow cells to switch in and out of the persister phenotype. Here, a different explanation is suggested for persistence, namely senescence. Using a mathematical model including age structure, it is shown that senescence provides a natural explanation for persistence-related phenomena, including the observations that the persister fraction depends on growth phase in batch culture and dilution rate in continuous culture.

[1]  W. Hillebrand Vanadium sulphide, patronite, and its mineral associates from Minasragra, Peru , 1907 .

[2]  F. O'grady,et al.  Trimodal Response of Escherichia coli and Proteus mirabilis to Penicillins , 1970, Nature.

[3]  H. Moyed,et al.  hipA, a newly recognized gene of Escherichia coli K-12 that affects frequency of persistence after inhibition of murein synthesis , 1983, Journal of bacteriology.

[4]  J. Cushing An introduction to structured population dynamics , 1987 .

[5]  W. G. Characklis,et al.  Transport of 1‐μm latex particles in pseudomonas aeruginosa biofilms , 1993 .

[6]  Martin Ackermann,et al.  Senescence in a Bacterium with Asymmetric Division , 2003, Science.

[7]  B. R. Levin,et al.  Phenotypic Tolerance: Antibiotic Enrichment of Noninherited Resistance in Bacterial Populations , 2005, Antimicrobial Agents and Chemotherapy.

[8]  D. Allison,et al.  Clonal variation in maximum specific growth rate and susceptibility towards antimicrobials , 2003, Journal of applied microbiology.

[9]  M. F.,et al.  Bibliography , 1985, Experimental Gerontology.

[10]  François Taddei,et al.  Aging and Death in an Organism That Reproduces by Morphologically Symmetric Division , 2005, PLoS Biology.

[11]  N. Vázquez-Laslop,et al.  Increased Persistence in Escherichia coli Caused by Controlled Expression of Toxins or Other Unrelated Proteins , 2006, Journal of bacteriology.

[12]  G. Webb Theory of Nonlinear Age-Dependent Population Dynamics , 1985 .

[13]  J. Bigger TREATMENT OF STAPHYLOCOCCAL INFECTIONS WITH PENICILLIN BY INTERMITTENT STERILISATION , 1944 .

[14]  Alfred J. Lotka,et al.  Studies on the mode of growth of material aggregates , 1907 .

[15]  H. Ceri,et al.  Persister cells mediate tolerance to metal oxyanions in Escherichia coli. , 2005, Microbiology.

[16]  S. Okabe,et al.  Uptake and release of inert fluorescence particles by mixed population biofilms. , 1997, Biotechnology and bioengineering.

[17]  Todd F. Dupont,et al.  Galerkin Methods in Age and Space for a Population Model with Nonlinear Diffusion , 1998, SIAM J. Numer. Anal..

[18]  N G Cogan,et al.  Effects of persister formation on bacterial response to dosing. , 2006, Journal of theoretical biology.

[19]  K. Lewis,et al.  Persister cells and tolerance to antimicrobials. , 2004, FEMS microbiology letters.

[20]  Bruce P. Ayati,et al.  A Multiscale Model of Biofilm as a Senescence-Structured Fluid , 2006, Multiscale Model. Simul..

[21]  M. R. Brown,et al.  Influence of growth rate on susceptibility to antimicrobial agents: biofilms, cell cycle, dormancy, and stringent response , 1990, Antimicrobial Agents and Chemotherapy.

[22]  M. Vulić,et al.  GlpD and PlsB Participate in Persister Cell Formation in Escherichia coli , 2006, Journal of bacteriology.

[23]  S. Leibler,et al.  Bacterial Persistence as a Phenotypic Switch , 2004, Science.

[24]  K. Lewis,et al.  Specialized Persister Cells and the Mechanism of Multidrug Tolerance in Escherichia coli , 2004, Journal of bacteriology.

[25]  Philip S. Stewart,et al.  Modeling Antibiotic Tolerance in Biofilms by Accounting for Nutrient Limitation , 2004, Antimicrobial Agents and Chemotherapy.

[26]  M. V. van Loosdrecht,et al.  Solids retention time in spherical biofilms in a biofilm airlift suspension reactor , 1994, Biotechnology and bioengineering.

[27]  A. M'Kendrick Applications of Mathematics to Medical Problems , 1925, Proceedings of the Edinburgh Mathematical Society.

[28]  Kendrick,et al.  Applications of Mathematics to Medical Problems , 1925, Proceedings of the Edinburgh Mathematical Society.

[29]  K. Lewis,et al.  Riddle of Biofilm Resistance , 2001, Antimicrobial Agents and Chemotherapy.

[30]  T. Nyström Bacterial senescence, programmed death, and premeditated sterility , 2005 .

[31]  W. McDermott Microbial persistence. , 1969, Harvey lectures.

[32]  Todd F. Dupont,et al.  Convergence of a step-doubling Galerkin method for parabolic problems , 1999, Mathematics of Computation.

[33]  Glenn F. Webb,et al.  α- and β-curves, sister-sister and mother-daughter correlations in cell population dynamics , 1989 .

[34]  P. Stewart,et al.  Modelling protection from antimicrobial agents in biofilms through the formation of persister cells. , 2005, Microbiology.

[35]  K. Lewis,et al.  Biofilms and Planktonic Cells of Pseudomonas aeruginosa Have Similar Resistance to Killing by Antimicrobials , 2001, Journal of bacteriology.

[36]  R. Walmsley,et al.  Replicative ageing in the fission yeast Schizosaccharomyces pombe , 1999, Yeast.

[37]  R. Mortimer,et al.  Life Span of Individual Yeast Cells , 1959, Nature.

[38]  Andreas Wagner,et al.  Faculty Opinions recommendation of Bacterial persistence: a model of survival in changing environments. , 2005 .