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The continuous morbidostat: A chemostat with controlled drug application to select for drug resistance mutants
1. | Department of Mathematics, Swinburne University of Technology, Melbourne VIC 3122, Australia |
2. | Department of Mathematics and National Center of Theoretical Science, National Tsing Hua University, Hsinchu, Taiwan |
3. | Department of Electrical Engineering, National Tsing Hua University, Hsinchu, Taiwan |
The morbidostat is a bacteria culture device that progressively increases antibiotic drug concentration and maintains a constant challenge for study of evolutionary pathway. The operation of a morbidostat under serial transfer has been analyzed previously. In this work, the global dynamics for the operation of a morbidostat under continuous dilution is analyzed. The device switches between drug on and drug off modes according to a simple threshold algorithm. We prove the extinction and uniform persistence of all species with both forward and backward mutations. Numerical simulations for the case of logistic growth and the Hill function for drug inhibition are also presented.
References:
[1] |
R. A. Armstrong and R. McGehee,
Competitive exclusion, Am. Nat., 115 (1980), 151-170.
doi: 10.1086/283553. |
[2] |
M. Barber, Infection by penicillin resistant Staphylococci, Lancet, 2 (1948), 641-644. Google Scholar |
[3] |
Z. Chen, S. B. Hsu and Y. T. Yang,
The Morbidostat: a bio-reactor that promotes selection for drug resistance in bacteria, SIAM J. Appl. Math., 77 (2017), 470-499.
doi: 10.1137/16M105695X. |
[4] |
K. S. Cheng, S. B. Hsu and S. S. Lin,
Some results on global stability of a predator-prey system, J. Math. Biology., 12 (1981), 115-126.
doi: 10.1007/BF00275207. |
[5] |
W. A. Coppel, Stability and Asymptotic Behavior of Differential Equations, Health. Math. Monograph, 1965. |
[6] |
J. B. Deris, M. Kim, Z. Zhang, H. Okano, R. Hermsen, A. Groisman and T. Hwa, The innate growth bistability and fitness landscapes of antibiotic resistant bacteria, Science, 342 (2013), 1237435. Google Scholar |
[7] |
M. Dragosits and D. Mattanovich, Adaptive laboratory evolution - principles and applications for biotechnology, Microb. Cell Fact., 12 (2013), 64. Google Scholar |
[8] |
R. Hermsen, J. B. Deris and T. Hwa, On the rapidity of antibiotic resistance evolution facilitated by a concentration gradient, Proc. Natl. Acad. Sci., 109 (2012), 10775-10780. Google Scholar |
[9] |
R. Hermsen and T. Hwa, Sources and Sinks: A stochastic model of evolution in heterogeneous environments, Phys. Rev. Lett., 105 (2015), 248104. Google Scholar |
[10] |
W. M. Hirsch, H. L. Smith and X. Q. Zhao,
Chain transitivity, attractivity and strong repellers for semidynamical systems, J. Dynam. Differential. Equations, 13 (2001), 107-131.
doi: 10.1023/A:1009044515567. |
[11] |
S. B. Hsu,
Limiting behavior for competing species system, SIAM J. Applied Math., 34 (1978), 760-763.
doi: 10.1137/0134064. |
[12] |
S. B. Hsu, Ordinary Differential Equations with Applications, World Scientific Press, 2013.
doi: 10.1142/8744.![]() ![]() |
[13] |
S. B. Hsu and P. E. Waltman,
Analysis of a model of two competitors in a chemostat with an external inhibitor, SIAM J. Applied Math., 52 (1992), 528-540.
doi: 10.1137/0152029. |
[14] |
A. H. Melnyk, A. Wong and R. Kassen, The fitness costs of antibiotic resistance mutations, Evol. Appl., 8 (2015), 273-283. Google Scholar |
[15] |
S. B. Levy and B. Marshall, Antibiotic resistance worldwide: causes, challenges and responses, Nat. Med., 10 (2004), s122–s129. Google Scholar |
[16] |
P. Liu, Y. T. Lee, C. Y. Wang and Y.-T. Yang, Design and use of a low cost, automated Morbidostat for adaptive evolution of bacteria under antibiotic drug selection, J. Vis. Exp., 115 (2016), e54426. Google Scholar |
[17] |
M. Mwangi, S. W. Wu and Y. Zhou, Tracking the in vivo evolution of jultidrug resistance in staphylococus aureus by whole genome sequencing, Pro. Natl. Acad. Sci., 104 (2007), 9451-9456. Google Scholar |
[18] |
H. L. Smith,
Bacterial competition in serial transfer culture, Math. Biosci., 229 (2011), 149-159.
doi: 10.1016/j.mbs.2010.12.001. |
[19] |
H. L. Smith and P. E. Waltman, The Theory of The Chemostat, Cambridge University Press, Cambridge, 1995.
doi: 10.1017/CBO9780511530043.![]() ![]() |
[20] |
E. Toprak, A. Veres, J. B. Mitchel, D. L. Hartl and R. Kishony, Evolutionary paths to antibiotic resistance under dynamically sustained drug selection, Nat. Genet., 44 (2012), 101-106. Google Scholar |
[21] |
A. Uri, An Introduction to System Biology Design Principles of Biological Circuits, Chapman and Hall Taylor and Francis Group, London, 2007. |
[22] |
X. Q. Zhao, Dynamical Systems in Population Biology, Springer, New York, 2015, 2nd Edition.
doi: 10.1007/978-0-387-21761-1. |
[23] |
Q. Zhang, G. Lambert, D. Liao, H. Kim, K. Robin, C. Tung, N. Pourmand and R. H. Austin, Acceleration of emergence of bacterial antibiotic resistance in connected microenvironment, Science, 333 (2011), 1764-1767. Google Scholar |
show all references
References:
[1] |
R. A. Armstrong and R. McGehee,
Competitive exclusion, Am. Nat., 115 (1980), 151-170.
doi: 10.1086/283553. |
[2] |
M. Barber, Infection by penicillin resistant Staphylococci, Lancet, 2 (1948), 641-644. Google Scholar |
[3] |
Z. Chen, S. B. Hsu and Y. T. Yang,
The Morbidostat: a bio-reactor that promotes selection for drug resistance in bacteria, SIAM J. Appl. Math., 77 (2017), 470-499.
doi: 10.1137/16M105695X. |
[4] |
K. S. Cheng, S. B. Hsu and S. S. Lin,
Some results on global stability of a predator-prey system, J. Math. Biology., 12 (1981), 115-126.
doi: 10.1007/BF00275207. |
[5] |
W. A. Coppel, Stability and Asymptotic Behavior of Differential Equations, Health. Math. Monograph, 1965. |
[6] |
J. B. Deris, M. Kim, Z. Zhang, H. Okano, R. Hermsen, A. Groisman and T. Hwa, The innate growth bistability and fitness landscapes of antibiotic resistant bacteria, Science, 342 (2013), 1237435. Google Scholar |
[7] |
M. Dragosits and D. Mattanovich, Adaptive laboratory evolution - principles and applications for biotechnology, Microb. Cell Fact., 12 (2013), 64. Google Scholar |
[8] |
R. Hermsen, J. B. Deris and T. Hwa, On the rapidity of antibiotic resistance evolution facilitated by a concentration gradient, Proc. Natl. Acad. Sci., 109 (2012), 10775-10780. Google Scholar |
[9] |
R. Hermsen and T. Hwa, Sources and Sinks: A stochastic model of evolution in heterogeneous environments, Phys. Rev. Lett., 105 (2015), 248104. Google Scholar |
[10] |
W. M. Hirsch, H. L. Smith and X. Q. Zhao,
Chain transitivity, attractivity and strong repellers for semidynamical systems, J. Dynam. Differential. Equations, 13 (2001), 107-131.
doi: 10.1023/A:1009044515567. |
[11] |
S. B. Hsu,
Limiting behavior for competing species system, SIAM J. Applied Math., 34 (1978), 760-763.
doi: 10.1137/0134064. |
[12] |
S. B. Hsu, Ordinary Differential Equations with Applications, World Scientific Press, 2013.
doi: 10.1142/8744.![]() ![]() |
[13] |
S. B. Hsu and P. E. Waltman,
Analysis of a model of two competitors in a chemostat with an external inhibitor, SIAM J. Applied Math., 52 (1992), 528-540.
doi: 10.1137/0152029. |
[14] |
A. H. Melnyk, A. Wong and R. Kassen, The fitness costs of antibiotic resistance mutations, Evol. Appl., 8 (2015), 273-283. Google Scholar |
[15] |
S. B. Levy and B. Marshall, Antibiotic resistance worldwide: causes, challenges and responses, Nat. Med., 10 (2004), s122–s129. Google Scholar |
[16] |
P. Liu, Y. T. Lee, C. Y. Wang and Y.-T. Yang, Design and use of a low cost, automated Morbidostat for adaptive evolution of bacteria under antibiotic drug selection, J. Vis. Exp., 115 (2016), e54426. Google Scholar |
[17] |
M. Mwangi, S. W. Wu and Y. Zhou, Tracking the in vivo evolution of jultidrug resistance in staphylococus aureus by whole genome sequencing, Pro. Natl. Acad. Sci., 104 (2007), 9451-9456. Google Scholar |
[18] |
H. L. Smith,
Bacterial competition in serial transfer culture, Math. Biosci., 229 (2011), 149-159.
doi: 10.1016/j.mbs.2010.12.001. |
[19] |
H. L. Smith and P. E. Waltman, The Theory of The Chemostat, Cambridge University Press, Cambridge, 1995.
doi: 10.1017/CBO9780511530043.![]() ![]() |
[20] |
E. Toprak, A. Veres, J. B. Mitchel, D. L. Hartl and R. Kishony, Evolutionary paths to antibiotic resistance under dynamically sustained drug selection, Nat. Genet., 44 (2012), 101-106. Google Scholar |
[21] |
A. Uri, An Introduction to System Biology Design Principles of Biological Circuits, Chapman and Hall Taylor and Francis Group, London, 2007. |
[22] |
X. Q. Zhao, Dynamical Systems in Population Biology, Springer, New York, 2015, 2nd Edition.
doi: 10.1007/978-0-387-21761-1. |
[23] |
Q. Zhang, G. Lambert, D. Liao, H. Kim, K. Robin, C. Tung, N. Pourmand and R. H. Austin, Acceleration of emergence of bacterial antibiotic resistance in connected microenvironment, Science, 333 (2011), 1764-1767. Google Scholar |










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