Inhibition of Mutation and Combating the Evolution of Antibiotic Resistance

The emergence of drug-resistant bacteria poses a serious threat to human health. In the case of several antibiotics, including those of the quinolone and rifamycin classes, bacteria rapidly acquire resistance through mutation of chromosomal genes during therapy. In this work, we show that preventing induction of the SOS response by interfering with the activity of the protease LexA renders pathogenic Escherichia coli unable to evolve resistance in vivo to ciprofloxacin or rifampicin, important quinolone and rifamycin antibiotics. We show in vitro that LexA cleavage is induced during RecBC-mediated repair of ciprofloxacin-mediated DNA damage and that this results in the derepression of the SOS-regulated polymerases Pol II, Pol IV and Pol V, which collaborate to induce resistance-conferring mutations. Our findings indicate that the inhibition of mutation could serve as a novel therapeutic strategy to combat the evolution of antibiotic resistance.

• Publication year

  2005

• Venue

  PLoS Biology

• Publication date

  2005-05-10

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1371/journal.pbio.0030176PMID 15869329PMCID 1088971
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• DNA Repair and Mutagenesis

  2006influential reference
• Error-prone replication for better or worse.

  2004cited by this paper
• Multiple pathways process stalled replication forks.

  2004cited by this paper
• Defining the position of the switches between replicative and bypass DNA polymerases

  2004cited by this paper
• SOS Response Induction by ß-Lactams and Bacterial Defense Against Antibiotic Lethality

  2004cited by this paper
• PriA Is Essential for Viability of the Escherichia coli Topoisomerase IV parE10(Ts) Mutant

  2004cited by this paper
• Situational Repair of Replication Forks

  2004cited by this paper
• Replication restart in gyrB Escherichia coli mutants

  2003cited by this paper
• Mutation Rate and Evolution of Fluoroquinolone Resistance in Escherichia coli Isolates from Patients with Urinary Tract Infections

  2003influential reference
• Antibiotic and chemotherapy : anti-infective agents and their use in therapy

  2003cited by this paper
• Molecular Epidemiology of Penicillin-Resistant and Ciprofloxacin-Resistant Streptococcus pneumoniae in Canada

  2003cited by this paper
• Error-Prone Polymerase, DNA Polymerase IV, Is Responsible for Transient Hypermutation during Adaptive Mutation in Escherichia coli

  2003cited by this paper
• The RuvAB Branch Migration Complex Can Displace Topoisomerase IV·Quinolone·DNA Ternary Complexes*

  2003cited by this paper
• Different Spectra of Stationary-Phase Mutations in Early-Arising versus Late-Arising Mutants of Pseudomonas putida: Involvement of the DNA Repair Enzyme MutY and the Stationary-Phase Sigma Factor RpoS

  2002cited by this paper
• SOS-induced DNA polymerases enhance long-term survival and evolutionary fitness

  2002cited by this paper
• Translesion DNA synthesis in eukaryotes: a one- or two-polymerase affair.

  2002cited by this paper
• Emerging fluoroquinolone-resistance for common clinically important gram-negative bacteria in Taiwan.

  2002cited by this paper
• Replication restart in UV‐irradiated Escherichia coli involving pols II, III, V, PriA, RecA and RecFOR proteins

  2002cited by this paper
• Risk factors for fluoroquinolone resistance in nosocomial Escherichia coli and Klebsiella pneumoniae infections.

  2002cited by this paper
• Specialized DNA Polymerases, Cellular Survival, and the Genesis of Mutations

  2002cited by this paper
• Direct rescue of stalled DNA replication forks via the combined action of PriA and RecG helicase activities.

  2002cited by this paper
• Antibiotic Persistence: The Role of Spontaneous DNA Repair Response

  2001influential reference
• Roles of chromosomal and episomal dinB genes encoding DNA pol IV in targeted and untargeted mutagenesis in Escherichia coli

  2001cited by this paper
• Stationary-phase mutation in the bacterial chromosome: Recombination protein and DNA polymerase IV dependence

  2001cited by this paper
• The tight linkage between DNA replication and double-strand break repair in bacteriophage T4

  2001influential reference
• Rescue of stalled replication forks by RecG: Simultaneous translocation on the leading and lagging strand templates supports an active DNA unwinding model of fork reversal and Holliday junction formation

  2001influential reference
• Evolving responsively: adaptive mutation

  2001cited by this paper
• Etoposide metabolites enhance DNA topoisomerase II cleavage near leukemia-associated MLL translocation breakpoints.

  2001cited by this paper
• INTRODUCTION - Links between recombination and replication: Vital roles of recombination

  2001cited by this paper
• Growth-dependent DNA breakage and cell death in a gyrase mutant of Salmonella.

  2001cited by this paper
• Roles of DNA polymerases V and II in SOS-induced error-prone and error-free repair in Escherichia coli

  2001cited by this paper
• Formation of Holliday junctions by regression of nascent DNA in intermediates containing stalled replication forks: RecG stimulates regression even when the DNA is negatively supercoiled

  2001influential reference
• Role of PriA in Replication Fork Reactivation inEscherichia coli

  2000cited by this paper
• Replication fork arrest and DNA recombination.

  2000cited by this paper
• The importance of repairing stalled replication forks

  2000cited by this paper
• The RecD subunit of the Escherichia coli RecBCD enzyme inhibits RecA loading, homologous recombination, and DNA repair.

  2000cited by this paper
• All three SOS‐inducible DNA polymerases (Pol II, Pol IV and Pol V) are involved in induced mutagenesis

  2000cited by this paper
• Roles of E. coli DNA polymerases IV and V in lesion-targeted and untargeted SOS mutagenesis

  2000cited by this paper
• Adaptive mutation: implications for evolution

  2000cited by this paper
• The processing of a Benzo(a)pyrene adduct into a frameshift or a base substitution mutation requires a different set of genes in Escherichia coli

  2000cited by this paper
• Determining mutation rates in bacterial populations.

  2000cited by this paper
• Analysis of topoisomerase function in bacterial replication fork movement: use of DNA microarrays.

  2000cited by this paper
• SOS mutator activity: unequal mutagenesis on leading and lagging strands.

  2000cited by this paper
• Replication fork assembly at recombination intermediates is required for bacterial growth.

  1999cited by this paper
• UmuD'(2)C is an error-prone DNA polymerase, Escherichia coli pol V.

  1999cited by this paper
• DNA Polymerase II (polB) Is Involved in a New DNA Repair Pathway for DNA Interstrand Cross-Links inEscherichia coli

  1999cited by this paper
• The Mechanism of Inhibition of Topoisomerase IV by Quinolone Antibacterials*

  1998cited by this paper
• Recombination and recombination-dependent DNA replication in bacteriophage T4.

  1998influential reference
• In Vivo Activities of Amoxicillin and Amoxicillin-Clavulanate against Streptococcus pneumoniae: Application to Breakpoint Determinations

  1998cited by this paper
• Laboratory Workhorse Decoded

  1997cited by this paper
• The complete genome sequence of Escherichia coli K-12.

  1997cited by this paper
• Multiple pathways for SOS-induced mutagenesis in Escherichia coli: an overexpression of dinB/dinP results in strongly enhancing mutagenesis in the absence of any exogenous treatment to damage DNA.

  1997cited by this paper
• DNA gyrase, topoisomerase IV, and the 4-quinolones

  1997cited by this paper
• Mutation in Escherichia coli under starvation conditions: a new pathway leading to small deletions in strains defective in mismatch correction

  1997cited by this paper
• DNA double‐strand breaks caused by replication arrest

  1997cited by this paper
• Adaptive mutations produce resistance to ciprofloxacin

  1997cited by this paper
• DNA gyrase and topoisomerase IV on the bacterial chromosome: quinolone-induced DNA cleavage.

  1996cited by this paper
• A class of gyrase mutants of Salmonella typhimurium show quinolone‐like lethality and require Rec functions for viability

  1995cited by this paper
• Relationship between quinolone use and emergence of ciprofloxacin-resistant Escherichia coli in bloodstream infections

  1995cited by this paper
• Mutants of Escherichia coli with increased fidelity of DNA replication.

  1993cited by this paper
• Function of the SOS Process in Repair of DNA Damage Induced by Modern 4‐Quinolones

  1993influential reference
• The role of the excision and error-prone repair systems in mutagenesis by fluorinated quinolones in Salmonella typhimurium.

  1992cited by this paper
• A short course in bacterial genetics

  1992cited by this paper
• Bound Lac repressor protein differentially inhibits the unwinding reactions catalyzed by DNA helicases.

  1992cited by this paper
• Quinolone resistance-determining region in the DNA gyrase gyrA gene of Escherichia coli

  1990cited by this paper
• Nucleotide excision repair in Escherichia coli.

  1990cited by this paper
• Nucleotide excision repair in Escherichia coli

  1990cited by this paper
• Isolation and characterization of noncleavable (Ind-) mutants of the LexA repressor of Escherichia coli K-12

  1988cited by this paper
• Correlation of antimicrobial pharmacokinetic parameters with therapeutic efficacy in an animal model.

  1988cited by this paper
• Role of RecA protein in untargeted UV mutagenesis of bacteriophage lambda: evidence for the requirement for the dinB gene.

  1986cited by this paper
• Spontaneous and mutagen-induced deletions: mechanistic studies in Salmonella tester strain TA102.

  1984cited by this paper
• Autodigestion of lexA and phage lambda repressors.

  1984cited by this paper
• Escherichia coli Mutants Thermosensitive for Deoxyribonucleic Acid Gyrase Subunit A: Effects on Deoxyribonucleic Acid Replication, Transcription, and Bacteriophage Growth

  1979cited by this paper
• Survival of recombination-deficient mutants of Escherichia coli during incubation with nalidixic acid

  1978cited by this paper

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• Function-specific epistasis shapes evolutionary trajectories towards antibiotic resistance

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• Targeting efflux pumps prevents the multi-step evolution of high-level resistance to fluoroquinolone in Pseudomonas aeruginosa

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• Ferrous gluconate triggers ferroptosis in Escherichia coli: Implications of lipid peroxidation and DNA damage.

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• The diverse phenotypic and mutational landscape induced by fluoroquinolone treatment

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• Two synonymous single-nucleotide polymorphisms promoting fluoroquinolone resistance of Escherichia coli in the environment.

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