Chapter 21 : The Biological Cost of Antibiotic Resistance

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This chapter focuses on the impact of antibiotic resistance caused by chromosomal mutations on bacterial fitness. An approach to estimate the biological costs associated with resistance is to use epidemiological data to prospectively follow the rate at which a patient infected with a resistant or susceptible bacterial strain transmits it to other people. Such experiments would allow one to measure the basic reproductive number, which is the most relevant parameter to use when predicting the relative rate of spread of the resistant and susceptible bacteria. Chromosomal mutations alter the intracellular level of the transcriptional regulator molecule ppGpp, which might cause additional pleiotrophic fitness effects. Certain mutational alterations in ribosomal protein S12 (encoded by the rpsL gene) causing streptomycin resistance reduce translational efficiency. In isoniazid-resistant , mutants with decreased fitness can be compensated by overproduction of another enzyme that may substitute for the defective catalase. But the most common compensation mechanism is restoration of the function itself, either by intragenic or extragenic mutations. A final implication emerging from studies of fitness costs and their genetic compensation concerns the development of new antibiotics. At present, the key parameter from a resistance development point of view that is considered by drug developers is the rate of appearance of the initial resistance mutation (or plasmid). Even though these rates do influence the rate of resistance development, their importance might be overestimated.

Citation: Andersson D, Patin S, Nilsson A, Kugelberg E. 2007. The Biological Cost of Antibiotic Resistance, p 339-348. In Bonomo R, Tolmasky M (ed), Enzyme-Mediated Resistance to Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555815615.ch21

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Class IIa Bacteriocin
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1. Austin, D. J., and, R. M. Anderson. 1999. Studies of antibiotic resistance within the patient, hospitals and the community using simple mathematical models. Philos Trans. R. Soc. Lond. B 354:721738.
2. Austin, D. J., and, R. M. Anderson. 1999. Transmission dynamics of epidemic methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci in England and Wales. J. Infect. Dis. 179:883891.
3. Austin, D. J.,, M. J. Bonten,, R. A. Weinstein,, S. Slaughter, and, R. M. Anderson. 1999. Vancomycin-resistant entero-cocci in intensive-care hospital settings: transmission dynamics, persistence, and the impact of infection control programs. Proc. Natl. Acad. Sci. USA 96:69086913.
4. Austin, D. J.,, K. G. Kristinsson, and, R. M. Anderson. 1999. The relationship between the volume of antimicrobial consumption in human communities and the frequency of resistance. Proc. Natl. Acad. Sci. USA 96:11521156.
5. Bagel, S.,, V. Hullen,, B. Wiedemann, and, P. Heisig. 1999. Impact of gyrA and parC mutations on quinolone resistance, doubling time, and supercoiling degree of Escherichia coli. Antimicrob. Agents. Chemother. 43:868875.
6. Billington, O. J.,, T. D. McHugh, and, S. H. Gillespie. 1999. Physiological cost of rifampin resistance induced in vitro in Mycobacterium tuberculosis. Antimicrob. Agents Che-mother. 43:18661869.
7. Björkholm, B.,, M. Sjolund,, P. G. Falk,, O. G. Berg,, L. Eng-strand, and, D. I. Andersson. 2001. Mutation frequency and biological cost of antibiotic resistance in Helicobacter pylori. Proc. Natl. Acad. Sci. USA 98:1460714612.
8. Björkman, J., and, D. I. Andersson. 2000. The cost of antibiotic resistance from a bacterial perspective. Drug. Resist. Updat. 3:237245.
9. Björkman, J.,, D. Hughes, and, D. I. Andersson. 1998. Virulence of antibiotic-resistant Salmonella typhimurium. Proc. Natl. Acad. Sci. USA 95:39493953.
10. Björkman, J.,, I. Nagaev,, O. G. Berg,, D. Hughes, and, D. I. Andersson. 2000. Effects of environment on compensatory mutations to ameliorate costs of antibiotic resistance. Science 287:14791482.
11. Björkman, J.,, P. Samuelsson,, D. I. Andersson, and, D. Hughes. 1999. Novel ribosomal mutations affecting translational accuracy, antibiotic resistance and virulence of Salmonella typhimurium. Mol. Microbiol. 31:5358.
12. Blower, S. M., and, J. L. Gerberding. 1998. Understanding, predicting and controlling the emergence of drug-resistant tuberculosis: a theoretical framework. J. Mol. Med. 76:624636.
13. Bottger, E. C.,, B. Springer,, M. Pletschette, and, P. Sander. 1998. Fitness of antibiotic-resistant microorganisms and compensatory mutations. Nat. Med. 4:13431344.
14. Cohen, T.,, B. Sommers, and, M. Murray. 2003. The effect of drug resistance on the fitness of Mycobacterium tuberculosis. Lancet Infect. Dis. 3:1321.
15. Compeau, G.,, B. J. Al-Achi,, E. Platsouka, and, S. B. Levy. 1988. Survival of rifampin-resistant mutants of Pseudomonas fluorescens and Pseudomonas putida in soil systems. Appl. Environ. Microbiol. 54:24322438.
16. Dykes, G. A., and, J. W. Hastings. 1998. Fitness costs associated with class IIa bacteriocin resistance in Listeria monocy-togenes B73. Lett. Appl. Microbiol. 26:58.
17. Elena, S. F. 2001. Evolutionary consequences and costs of plasmid-borne resistance to antibiotics, p. 163180. In D. Hughes and, D. I. Andersson (ed.), Antibiotic Development and Resistance. Taylor and Francis, London, United Kingdom.
18. Enne, V. I.,, D. M. Livermore,, P. Stephens, and, L. M. Hall. 2001. Persistence of sulphonamide resistance in Escherichia coli in the UK despite national prescribing restriction. Lancet 357:13251328.
19. Fermer, C., and, G. Swedberg. 1997. Adaptation to sulfon-amide resistance in Neisseria meningitidis may have required compensatory changes to retain enzyme function: kinetic analysis of dihydropteroate synthases from N. meningitidis expressed in a knockout mutant of Escherichia coli. J. Bacteriol. 179:831837.
20. Ferry, S., and, L. G. Burman. 1987. Urinary tract infection in primary health care in northern Sweden. Scand. J. Prim. Health Care 5:233240.
21. Folkesson, A. 2002. On Extrinsic and Intrinsic Organizational Themes in Gram-Negative Bacteria and Their Role in Evolution and Virulence of the Bacterial Genus Salmonella spp. Doctoral thesis, Karolinska Institutet, Stockholm, Sweden.
22. Garcia-Bustos, J., and, A. Tomasz. 1990. A biological price of antibiotic resistance: major changes in the peptidoglycan structure of penicillin-resistant pneumococci. Proc. Natl. Acad. Sci. USA 87:54155419.
23. Gillespie, S. H.,, O. J. Billington,, A. Breathnach, and, T. D. McHugh. 2002. Multiple drug-resistant Mycobacterium tuberculosis: evidence for changing fitness following passage through human hosts. Microb. Drug. Resist. 8:273279.
24. Gillespie, S. H.,, L. L. Voelker, and, A. Dickens. 2002. Evolutionary barriers to quinolone resistance in Streptococcus pneumoniae. Microb. Drug. Resist. 8:7984.
25. Goldman, W. E., and, B. T. Cookson. 1988. Structure and functions of the Bordetella tracheal cytotoxin. Tokai. J. Exp. Clin. Med. 13 (Suppl.):187191.
26. Gustafsson, I.,, O. Cars, and, D. I. Andersson. 2003. Fitness of antibiotic resistant Staphylococcus epidermidis assessed by competition on the skin of human volunteers. J. Antimicrob. Chemother. 52:258263.
27. Heym, B.,, E. Stavropoulos,, N. Honore,, P. Domenech,, B. Saint-Joanis,, T. M. Wilson,, D. M. Collins,, M. J. Colston, and, S. T. Cole. 1997. Effects of overexpression of the alkyl hydroperoxide reductase AhpC on the virulence and isonia-zid resistance of Mycobacterium tuberculosis. Infect. Immun. 65:13951401.
28. Johanson, U.,, A. Aevarsson,, A. Liljas, and, D. Hughes. 1996. The dynamic structure of EF-G studied by fusidic acid resistance and internal revertants. J. Mol. Biol. 258:420432.
29. Kataja, J.,, P. Huovinen,, A. Muotiala,, J. Vuopio-Varkila,, A. Efstratiou,, G. Hallas,, H. Seppala, et al. 1998. Clonal spread of group A Streptococcus with the new type of erythromycin resistance. J. Infect. Dis. 177:786789.
30. Kristinsson, K. G. 1997. Effect of antimicrobial use and other risk factors on antimicrobial resistance in pneumococci. Microb. Drug. Resist. 3:117123.
31. Levin, B. R. 2001. Minimizing potential resistance: a population dynamics view. Clin. Infect. Dis. 33(Suppl. 3): S161S169.
32. Levin, B. R. 2002. Models for the spread of resistant pathogens. Neth. J. Med. 60:58–64, 64–66.
33. Levin, B. R.,, M. Lipsitch,, V. Perrot,, S. Schrag,, R. Antia,, L. Simonsen,, N. M. Walker, and, F. M. Stewart. 1997. The population genetics of antibiotic resistance. Clin. Infect. Dis. 24(Suppl. 1):S9S16.
34. Levin, B. R.,, V. Perrot, and, N. Walker. 2000. Compensatory mutations, antibiotic resistance and the population genetics of adaptive evolution in bacteria. Genetics 154:985997.
35. Levy, S. B. 1992. The Antibiotic Paradox: How Miracle Drugs Are Destroying the Miracle. Plenum Press, New York, N.Y.
36. Li, Z.,, C. Kelley,, F. Collins,, D. Rouse, and, S. Morris. 1998. Expression of katG in Mycobacterium tuberculosis is associated with its growth and persistence in mice and guinea pigs. J. Infect. Dis. 177:10301035.
37. Lindberg, F.,, S. Lindquist, and, S. Normark. 1987. Inactiva-tion of the ampD gene causes semiconstitutive overproduction of the inducible Citrobacter freundii beta-lactamase. J. Bacteriol. 169:19231928.
38. Lipsitch, M. 2001. The rise and fall of antimicrobial resistance. Trends Microbiol. 9:438444.
39. Lipsitch, M.,, C. T. Bergstrom, and, B. R. Levin. 2000. The epidemiology of antibiotic resistance in hospitals: paradoxes and prescriptions. Proc. Natl. Acad. Sci. USA 97:19381943.
40. MacVanin, M.,, U. Johanson,, M. Ehrenberg, and, D. Hughes. 2000. Fusidic acid-resistant EF-G perturbs the accumulation of ppGpp. Mol. Microbiol. 37:98107.
41. Maisnier-Patin, S.,, O. G. Berg,, L. Liljas, and, D. I. Andersson. 2002. Compensatory adaptation to the deleterious effect of antibiotic resistance in Salmonella typhimurium. Mol. Microbiol. 46:355366.
42. Massey, R. C.,, A. Buckling, and, S. J. Peacock. 2001. Phenotypic switching of antibiotic resistance circumvents permanent costs in Staphylococcus aureus. Curr. Biol. 11:18101814.
43. McCormick, J. B. 1998. Epidemiology of emerging/re-emerging antimicrobial-resistant bacterial pathogens. Curr. Opin. Microbiol. 1:125129.
44. Nagaev, I.,, J. Björkman,, D. I. Andersson, and, D. Hughes. 2001. Biological cost and compensatory evolution in fusidic acid-resistant Staphylococcus aureus. Mol. Microbiol. 40:433439.
45. Nilsson, A.,, O. G. Berg,, O. Aspewall,, G. Kahlmeter, and, D. I. Andersson. 2003. Biological costs and mechanisms of fos-fomycin resistance in Escherichia coli. Antimicrob. Agents Chemother. 47:28502858.
46. Normark, S. 1995. beta-Lactamase induction in gram-negative bacteria is intimately linked to peptidoglycan recycling. Microb. Drug. Resist. 1:111114.
47. Pym, A. S.,, B. Saint-Joanis, and, S. T. Cole. 2002. Effect of katG mutations on the virulence of Mycobacterium tuberculosis and the implication for transmission in humans. Infect. Immun. 70:49554960.
48. Radstrom, P.,, G. Swedberg, and, O. Skold. 1991. Genetic analyses of sulfonamide resistance and its dissemination in gram-negative bacteria illustrate new aspects of R plasmid evolution. Antimicrob. Agents Chemother. 35:18401848.
49. Reynolds, M. G. 2000. Compensatory evolution in rifampin-resistant Escherichia coli. Genetics 156:14711481.
50. Sanchez, P.,, J. F. Linares,, B. Ruiz-Diez,, E. Campanario,, A. Navas,, F. Baquero, and, J. L. Martinez. 2002. Fitness of in vitro selected Pseudomonas aeruginosa nalB and nfxB multidrug resistant mutants. J. Antimicrob. Chemother. 50:657664.
51. Sander, P.,, B. Springer,, T. Prammananan,, A. Sturmfels,, M. Kappler,, M. Pletschette, and, E. C. Bottger. 2002. Fitness cost of chromosomal drug resistance-conferring mutations. Antimicrob. Agents. Chemother. 46:12041211.
52. Schrag, S. J., and, V. Perrot. 1996. Reducing antibiotic resistance. Nature 381:120121.
53. Schrag, S. J.,, V. Perrot, and, B. R. Levin. 1997. Adaptation to the fitness costs of antibiotic resistance in Escherichia coli. Proc. R. Soc. Lond. B 264:12871291.
54. Seppala, H.,, T. Klaukka,, J. Vuopio-Varkila,, A. Muotiala,, H. Helenius,, K. Lager,, P. Huovinen, et al. 1997. The effect of changes in the consumption of macrolide antibiotics on erythromycin resistance in group A streptococci in Finland. N. Engl. J. Med. 337:441446.
55. Sherman, D. R.,, K. Mdluli,, M. J. Hickey,, T. M. Arain,, S. L. Morris,, C. E. Barry III, and, C. K. Stover. 1996. Compensatory ahpC gene expression in isoniazid-resistant Mycobacterium tuberculosis. Science 272:16411643.
56. Sjölund, M.,, K. Wreiber,, D. I. Andersson,, M. J. Blaser, and, L. Engstrand. 2003. Long-term persistence of resistant Enterococcus species after antibiotic to eradicate Helicobacter pylori. Ann. Intern. Med. 139:483487.
57. Wichelhaus, T. A.,, B. Boddinghaus,, S. Besier,, V. Schafer,, V. Brade, and, A. Ludwig. 2002. Biological cost of rifampin resistance from the perspective of Staphylococcus aureus. Antimicrob. Agents Chemother. 46:33813385.
58. Wilson, T. M.,, G. W. de Lisle, and, D. M. Collins. 1995. Effect of inhA and katG on isoniazid resistance and virulence of Mycobacterium bovis. Mol. Microbiol. 15:10091015.


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Table 21.1

Examples of cases in which biological costs of chromosomal resistances have been estimated

Citation: Andersson D, Patin S, Nilsson A, Kugelberg E. 2007. The Biological Cost of Antibiotic Resistance, p 339-348. In Bonomo R, Tolmasky M (ed), Enzyme-Mediated Resistance to Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555815615.ch21
Generic image for table
Table 21.2

Examples of cases in which genetic compensation of fitness cost caused by chromosomal mutations has been demonstrated or inferred

Citation: Andersson D, Patin S, Nilsson A, Kugelberg E. 2007. The Biological Cost of Antibiotic Resistance, p 339-348. In Bonomo R, Tolmasky M (ed), Enzyme-Mediated Resistance to Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555815615.ch21

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