Lethal Mutagenesis of Bacteria

Lethal mutagenesis, the killing of a microbial pathogen with a chemical mutagen, is a potential broad-spectrum antiviral treatment. It operates by raising the genomic mutation rate to the point that the deleterious load causes the population to decline. Its use has been limited to RNA viruses because of their high intrinsic mutation rates. Microbes with DNA genomes, which include many viruses and bacteria, have not been considered for this type of treatment because their low intrinsic mutation rates seem difficult to elevate enough to cause extinction. Surprisingly, models of lethal mutagenesis indicate that bacteria may be candidates for lethal mutagenesis. In contrast to viruses, bacteria reproduce by binary fission, and this property ensures their extinction if subjected to a mutation rate >0.69 deleterious mutations per generation. The extinction threshold is further lowered when bacteria die from environmental causes, such as washout or host clearance. In practice, mutagenesis can require many generations before extinction is achieved, allowing the bacterial population to grow to large absolute numbers before the load of deleterious mutations causes the decline. Therefore, if effective treatment requires rapid population decline, mutation rates ≫0.69 may be necessary to achieve treatment success. Implications for the treatment of bacteria with mutagens, for the evolution of mutator strains in bacterial populations, and also for the evolution of mutation rate in cancer are discussed.

[1]  Pedro R. Lowenstein,et al.  Response of Foot-and-Mouth Disease Virus to Increased Mutagenesis: Influence of Viral Load and Fitness in Loss of Infectivity , 2000, Journal of Virology.

[2]  M. Huynen,et al.  Neutral evolution of mutational robustness. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[3]  J. Drake,et al.  Rates of spontaneous mutation. , 1998, Genetics.

[4]  J. Coffin,et al.  The solitary wave of asexual evolution , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[5]  P. Sniegowski Evolution: Setting the mutation rate , 1997, Current Biology.

[6]  Marco Vignuzzi,et al.  Ribavirin and lethal mutagenesis of poliovirus: molecular mechanisms, resistance and biological implications. , 2005, Virus research.

[7]  J. Drake Rates of spontaneous mutation among RNA viruses. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[8]  C. Wilke,et al.  The traveling-wave approach to asexual evolution: Muller's ratchet and speed of adaptation. , 2007, Theoretical population biology.

[9]  Blake R. Peterson,et al.  Lethal Mutagenesis of Picornaviruses with N-6-Modified Purine Nucleoside Analogues , 2008, Antimicrobial Agents and Chemotherapy.

[10]  C. Wilke,et al.  Thermodynamics of Neutral Protein Evolution , 2006, Genetics.

[11]  T. Johnson Beneficial mutations, hitchhiking and the evolution of mutation rates in sexual populations. , 1999, Genetics.

[12]  J. Haigh The accumulation of deleterious genes in a population--Muller's Ratchet. , 1978, Theoretical population biology.

[13]  Eric J. Deeds,et al.  Semiconservative replication in the quasispecies model. , 2003, Physical review. E, Statistical, nonlinear, and soft matter physics.

[14]  C. Wilke,et al.  Predicting the tolerance of proteins to random amino acid substitution. , 2005, Biophysical journal.

[15]  E. Domingo,et al.  Molecular indetermination in the transition to error catastrophe: Systematic elimination of lymphocytic choriomeningitis virus through mutagenesis does not correlate linearly with large increases in mutant spectrum complexity , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[16]  R. Lenski,et al.  Evolution of high mutation rates in experimental populations of E. coli , 1997, Nature.

[17]  J. W. Campbell,et al.  Experimental Determination and System Level Analysis of Essential Genes in Escherichia coli MG1655 , 2003, Journal of bacteriology.

[18]  P. Feldman Evolution of sex , 1975, Nature.

[19]  Eugene I. Shakhnovich,et al.  Protein stability imposes limits on organism complexity and speed of molecular evolution , 2007, Proceedings of the National Academy of Sciences.

[20]  A. Perelson,et al.  Complete genetic linkage can subvert natural selection , 2007, Proceedings of the National Academy of Sciences.

[21]  D. Gessler,et al.  The constraints of finite size in asexual populations and the rate of the ratchet. , 1995, Genetical research.

[22]  Rafael Sanjuán,et al.  The distribution of fitness effects caused by single-nucleotide substitutions in an RNA virus. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[23]  R. H.J.MULLE THE RELATION OF RECOMBINATION TO MUTATIONAL ADVANCE , 2002 .

[24]  Y. Yano,et al.  Application of logistic growth model to pharmacodynamic analysis of in vitro bactericidal kinetics. , 1998, Journal of pharmaceutical sciences.

[25]  C. Wilke SELECTION FOR FITNESS VERSUS SELECTION FOR ROBUSTNESS IN RNA SECONDARY STRUCTURE FOLDING , 2001, Evolution; international journal of organic evolution.

[26]  J. J. Bull,et al.  Theory of Lethal Mutagenesis for Viruses , 2007, Journal of Virology.

[27]  Edward C. Cox,et al.  Transposable elements as mutator genes in evolution , 1983, Nature.

[28]  J. Mullins,et al.  Lethal mutagenesis of HIV with mutagenic nucleoside analogs. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[29]  Ricard V Solé,et al.  The Fittest versus the Flattest: Experimental Confirmation of the Quasispecies Effect with Subviral Pathogens , 2006, PLoS pathogens.

[30]  J. Collins,et al.  A Common Mechanism of Cellular Death Induced by Bactericidal Antibiotics , 2007, Cell.

[31]  Emmanuel Tannenbaum,et al.  Semiconservative replication, genetic repair, and many-gened genomes: Extending the quasispecies paradigm to living systems , 2005 .

[32]  C. Cameron,et al.  Lethal mutagens: broad-spectrum antivirals with limited potential for development of resistance? , 2004, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[33]  R. Lenski,et al.  Epistatic effects of promoter and repressor functions of the Tn10 tetracycline‐resistance operon on the fitness of Escherichia coli , 1994, Molecular ecology.

[34]  C. Cameron,et al.  Mechanisms of action of ribavirin against distinct viruses , 2005, Reviews in medical virology.

[35]  M. Kimura,et al.  The mutational load with epistatic gene interactions in fitness. , 1966, Genetics.

[36]  Juno Choe,et al.  Protein tolerance to random amino acid change. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[37]  L. Loeb,et al.  Viral error catastrophe by mutagenic nucleosides. , 2004, Annual review of microbiology.

[38]  T Kibota,et al.  Estimate of the genomic mutation rate deleterious to overall fitness in E. coli , 1996 .

[39]  Julie K. Pfeiffer,et al.  A single mutation in poliovirus RNA-dependent RNA polymerase confers resistance to mutagenic nucleotide analogs via increased fidelity , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[40]  E. Domingo,et al.  Efficient Virus Extinction by Combinations of a Mutagen and Antiviral Inhibitors , 2001, Journal of Virology.

[41]  Frances H Arnold,et al.  Why high-error-rate random mutagenesis libraries are enriched in functional and improved proteins. , 2004, Journal of molecular biology.

[42]  B. Godelle,et al.  The Evolution of Mutation Rate in Finite Asexual Populations , 2006, Genetics.

[43]  P. Sniegowski,et al.  Fitness evolution and the rise of mutator alleles in experimental Escherichia coli populations. , 2002, Genetics.

[44]  Christoph Adami,et al.  Selection for mutational robustness in finite populations. , 2006, Journal of theoretical biology.

[45]  Art Poon,et al.  COMPENSATING FOR OUR LOAD OF MUTATIONS: FREEZING THE MELTDOWN OF SMALL POPULATIONS , 2000, Evolution; international journal of organic evolution.

[46]  Blake R. Peterson,et al.  Lethal Mutagenesis of Poliovirus Mediated by a Mutagenic Pyrimidine Analogue , 2007, Journal of Virology.

[47]  C. Ofria,et al.  Evolution of digital organisms at high mutation rates leads to survival of the flattest , 2001, Nature.

[48]  F. Taddei,et al.  Role of mutator alleles in adaptive evolution , 1997, Nature.

[49]  Al Bartolucci,et al.  Ribavirin Reveals a Lethal Threshold of Allowable Mutation Frequency for Hantaan Virus , 2007, Journal of Virology.

[50]  R. Siegel,et al.  Generation of large libraries of random mutants in Bacillus subtilis by PCR-based plasmid multimerization. , 1997, BioTechniques.

[51]  L. Loeb,et al.  Lethal mutagenesis of HIV. , 2005, Virus research.

[52]  T. Johnson The approach to mutation–selection balance in an infinite asexual population, and the evolution of mutation rates , 1999, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[53]  G. Georgiou,et al.  Quantitative analysis of the effect of the mutation frequency on the affinity maturation of single chain Fv antibodies. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[54]  Christoph Adami,et al.  Thermodynamic prediction of protein neutrality. , 2004, Proceedings of the National Academy of Sciences of the United States of America.