Hypermutable bacteria isolated from humans – a critical analysis

Hall, Lucinda M. C.; Henderson-Begg, Stephanie

doi:10.1099/mic.0.29079-0

Cited by 80 publications

(61 citation statements)

References 56 publications

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“…In contrast, the MC mutY mutants exhibited a more pronounced mutator phenotype than the MC mutS-deficient strain (Table 2) (10,11). MutS null mutants in other mucosal pathogens, such as Streptococcus pneumoniae and Haemophilus influenzae, have also been reported to exhibit low mutation frequencies compared to wild-type strains (22,39,60). These results indicate that a different strategy for preventing spontaneous mutations may have developed in the MC and other mucosal pathogens compared to E. coli.…”

Section: Discussioncontrasting

confidence: 40%

“…This assay does not allow for the measurement of mutation rates as do Luria-Delbrück-like fluctuation experiments (34), and the assay is not sensitive enough to ascertain the significance of slight variations in mutagenicity. However, this relatively quick method of determining mutation frequencies is widely used among researchers and allows for possible comparisons of results among different laboratories (22).…”

Section: Methodsmentioning

confidence: 99%

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Genetic Interactions of DNA Repair Pathways in the PathogenNeisseria meningitidis

et al. 2007

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The current increase in the incidence and severity of infectious diseases mandates improved understanding of the basic biology and DNA repair profiles of virulent microbes. In our studies of the major pathogen and model organism Neisseria meningitidis, we constructed a panel of mutants inactivating genes involved in base excision repair, mismatch repair, nucleotide excision repair (NER), translesion synthesis, and recombinational repair pathways. The highest spontaneous mutation frequency among the N. meningitidis single mutants was found in the MutY-deficient strain as opposed to mutS mutants in Escherichia coli, indicating a role for meningococcal MutY in antibiotic resistance development. Recombinational repair was recognized as a major pathway counteracting methyl methanesulfonate-induced alkylation damage in the N. meningitidis. In contrast to what has been shown in other species, meningococcal NER did not contribute significantly to repair of alkylation-induced DNA damage, and meningococcal recombinational repair may thus be one of the main pathways for removal of abasic (apurinic/apyrimidinic) sites and strand breaks in DNA. Conversely, NER was identified as the main meningococcal defense pathway against UV-induced DNA damage. N. meningitidis RecA single mutants exhibited only a moderate decrease in survival after UV exposure as opposed to E. coli recA strains, which are extremely UV sensitive, possibly reflecting the lack of a meningococcal SOS response. In conclusion, distinct differences between N. meningitidis and established DNA repair characteristics in E. coli and other species were identified.Neisseria meningitidis, or the meningococcus (MC), is a gram-negative inhabitant of the human oropharynx that may disseminate into the bloodstream and traverse the blood-brain barrier to cause septicemia and/or meningitis. MC cells residing on mucosal surfaces are exposed to DNA damaging agents, in particular, reactive oxygen species (ROS) generated from normal cellular metabolism or a highly effective immune system through the oxidative burst. ROS from exogenous and endogenous sources can induce a vast number of different types of DNA damage, including single-and double-strand breaks, abasic (apurinic/apyrimidinic, or AP) sites, and base damages, among which the oxidation product of guanine, 7,8-dihydro-8-oxo-2Ј-deoxyguanosine (8oxoG), is one of the most frequent (13). Oxidative DNA damage is primarily processed by the base excision repair (BER) pathway (52). In Escherichia coli, BER is initiated by DNA glycosylases that nick the Nglycosylic bond and remove the damaged base by a flipping mechanism. The remaining sugar and phosphate moieties are subsequently excised either by an AP-lyase activity inherent in many DNA glycosylases or by an AP endonuclease, leaving the processing of the 3Ј or 5Ј terminus, respectively, to a deoxyribose phosphodiesterase (52). A triplet of enzymes referred to as the GO system composed of the DNA glycosylases MutY and Fpg, as well as the nucleotide hydrolase MutT, is involved in ...

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Section: Discussioncontrasting

confidence: 40%

Section: Methodsmentioning

confidence: 99%

Genetic Interactions of DNA Repair Pathways in the PathogenNeisseria meningitidis

et al. 2007

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“…As noted above, the use of hypermutator strains can help to reveal the range of endogenous resistance. While these can give up to 1,000-fold higher resistance frequencies than normal (256), their use may be particularly relevant, since a significant percentage of antibiotic-resistant clinical isolates, especially those from chronic infections, have been shown to be hypermutable strains (138,146,241,256,359). The pressure of selection for mutations will itself select for hypermutators (235).…”

Section: Assessing Endogenous Resistance Potentialmentioning

confidence: 99%

Challenges of Antibacterial Discovery

Silver¹

2011

Clin Microbiol Rev

1,155

961

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SUMMARY The discovery of novel small-molecule antibacterial drugs has been stalled for many years. The purpose of this review is to underscore and illustrate those scientific problems unique to the discovery and optimization of novel antibacterial agents that have adversely affected the output of the effort. The major challenges fall into two areas: (i) proper target selection, particularly the necessity of pursuing molecular targets that are not prone to rapid resistance development, and (ii) improvement of chemical libraries to overcome limitations of diversity, especially that which is necessary to overcome barriers to bacterial entry and proclivity to be effluxed, especially in Gram-negative organisms. Failure to address these problems has led to a great deal of misdirected effort.

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“…the mutator definition applied, and the bacterial species analyzed (7,15,36,38). Although various species, including P. aeruginosa, S. aureus, and H. influenzae (7,36,38), have been analyzed, there are no data regarding the mutator strength of TD-SCVs, the S. aureus phenotype that in contrast to the normal phenotype is isolated primarily from respiratory specimens from older CF patients with advanced disease (5).…”

Section: Vol 52 2008 Thymidine-dependent S Aureus Scvs Are Hypermumentioning

confidence: 99%

The Thymidine-Dependent Small-Colony-Variant Phenotype Is Associated with Hypermutability and Antibiotic Resistance in Clinical Staphylococcus aureus Isolates

Besier

Zander

Kahl

et al. 2008

Antimicrob Agents Chemother

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Thymidine-dependent small-colony variants (TD-SCVs) of Staphylococcus aureus can be isolated from the airway secretions of patients suffering from cystic fibrosis (CF) and are implicated in persistent and treatmentresistant infections. These characteristics, as well as the variety of mutations in the thymidylate synthaseencoding thyA gene which are responsible for thymidine dependency, suggest that these morphological variants are hypermutable. To prove this hypothesis, we analyzed the mutator phenotype of different S. aureus phenotypes, in particular CF-derived TD-SCVs, CF-derived isolates with a normal phenotype (NCVs), and non-CF NCVs. The comparative analysis revealed that the CF isolates had significantly higher mutation rates than the non-CF isolates. The TD-SCVs, in turn, harbored significantly more strong hypermutators (mutation rate > 10 ؊7 ) than the CF and non-CF NCVs. In addition, antimicrobial resistance to non-beta-lactam antibiotics, including gentamicin, ciprofloxacin, erythromycin, fosfomycin, and rifampin, was significantly more prevalent in TD-SCVs than in CF and non-CF NCVs. Interestingly, macrolide resistance, which is usually mediated by mobile genetic elements, was conferred in half of the macrolide-resistant TD-SCVs by the point mutation A2058G or A2058T in the genes encoding the 23S rRNA. Sequence analysis of mutS and mutL, which are involved in DNA mismatch repair in gram-positive bacteria, revealed that in hypermutable CF isolates and especially in TD-SCVs, mutL was often truncated due to frameshift mutations. In conclusion, these data provide direct evidence that TD-SCVs are hypermutators. This hypermutability apparently favors the acquisition of antibiotic resistance and facilitates bacterial adaptation during long-term persistence.

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Hypermutable bacteria isolated from humans – a critical analysis

Cited by 80 publications

References 56 publications

Genetic Interactions of DNA Repair Pathways in the PathogenNeisseria meningitidis

Genetic Interactions of DNA Repair Pathways in the PathogenNeisseria meningitidis

Challenges of Antibacterial Discovery

The Thymidine-Dependent Small-Colony-Variant Phenotype Is Associated with Hypermutability and Antibiotic Resistance in Clinical Staphylococcus aureus Isolates

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