Compensatory Evolution of pbp Mutations Restores the Fitness Cost Imposed by β-Lactam Resistance in Streptococcus pneumoniae

Orio, Andrea Georgina Albarracín; Piñas, Germán E.; Cortes, Paulo R.; Cian, Melina B.; Echenique, José

doi:10.1371/journal.ppat.1002000

Cited by 69 publications

(44 citation statements)

References 44 publications

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“…Surprisingly, in spite of the amoxicillin-clavulanic acid pressure on the six persistent pneumococci resistant to amoxicillin-clavulanic acid, neither new recombination events nor point mutations in the pbp2b of the resistant strains were observed. These results suggest that an optimal combination of pbp genes is maintained to compensate for the fitness cost imposed by additional changes in these genes, either by point mutation or recombination, as has previously been shown (1).…”

Section: Discussionsupporting

confidence: 74%

Pneumococci Can Persistently Colonize Adult Patients with Chronic Respiratory Disease

et al. 2012

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d; and Consejo Superior de Investigaciones Científicas, Madrid, Spain e Streptococcus pneumoniae plays an important role in causing acute exacerbations in patients with chronic respiratory disease. However, few data are available regarding pneumococcal persistence in adult patients with chronic respiratory diseases. Fifty pneumococci recovered from sputum samples (1995 to 2010) from 13 adult patients with >3 episodes of acute exacerbation or pneumonia, with the same serotype and pulsed-field gel electrophoresis (PFGE) pattern, were studied. Multilocus sequence typing (MLST) loci, penicillin-binding protein (PBP) genes (pbp2x, pbp1a, pbp2b), and the quinolone-resistant determining regions (QRDRs) of parC, parE, and gyrA were PCR amplified and sequenced. The average time between the first and last episode was 582 days (standard deviation [SD], ؎362). All but two patients received multiple courses of ␤-lactam treatment, and all persistent strains were resistant to penicillin; however, the PBP sequences were stable over time apart from one variable nucleotide in pbp2x, observed among pneumococci isolated from three patients. In contrast, 7/11 patients treated with fluoroquinolones had fluoroquinolone-resistant pneumococci. In three patients, the initially fluoroquinolone-susceptible strain developed resistance after fluoroquinolone therapy, and in the remaining four patients, the persistent strain was fluoroquinolone resistant from the first episode. QRDR changes involved in fluoroquinolone resistance were frequently observed in persistent strains after fluoroquinolone treatment; however, the PBP sequences and MLST genotypes of these strains were stable over time. Patients with chronic respiratory disease, such as chronic obstructive pulmonary disease (COPD) and bronchiectasis, are often persistently colonized by respiratory pathogens (27, 32). Airway colonization, mainly by Pseudomonas aeruginosa, Haemophilus influenzae, and Streptococcus pneumoniae, contributes to progressive pulmonary damage, increasing the morbidity and the risk of death of these patients due to frequent and recurrent episodes of acute exacerbations (27).Most of the acute exacerbations caused by P. aeruginosa are due to a preexisting strain which colonizes the lower airway. Often, these strains are hypermutable (strains with defects in genes involved in DNA repair) and have been related to an increase of antimicrobial resistance due to a stepwise accumulation of point mutations (28). In contrast, when S. pneumoniae has been recovered during an acute exacerbation, this has generally been associated with the acquisition of a new strain, and the high prevalence of multidrug-resistant pneumococci associated with acute exacerbations has been related to the consumption of antimicrobials that these patients receive as empirical treatment (18, 26). The role of pneumococcal hypermutable strains is unclear and could be related to the persistent strains that colonize among 15 to 17% of COPD patients at any time (12,32).Antimicrobial treatment for acute exa...

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Section: Discussionsupporting

confidence: 74%

Pneumococci Can Persistently Colonize Adult Patients with Chronic Respiratory Disease

et al. 2012

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“…In support of this, Albarracín Orio et al (50) observed that incorporation of pbp2b mutant alleles from commensal streptococci resulted in fitness costs. Incorporation of pbp1a and pbp2x mutant alleles, however, had a compensatory effect, which may explain why most resistant pneumococci are altered in all three pbp genes.…”

Section: Discussionmentioning

confidence: 90%

Commensal Streptococci Serve as a Reservoir for β-Lactam Resistance Genes in Streptococcus pneumoniae

Jensen

Valdórsson

Frimodt‐Møller

et al. 2015

Antimicrob Agents Chemother

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c Streptococcus pneumoniae is a leading cause of pneumonia, meningitis, septicemia, and middle ear infections. The incidence of S. pneumoniae isolates that are not susceptible to penicillin has risen worldwide and may be above 20% in some countries. Betalactam antibiotic resistance in pneumococci is associated with significant sequence polymorphism in penicillin-binding proteins (PBPs). Commensal streptococci, especially S. mitis and S. oralis, have been identified as putative donors of mutated gene fragments. However, no studies have compared sequences of the involved pbp genes in large collections of commensal streptococci with those of S. pneumoniae. We therefore investigated the sequence diversity of the transpeptidase region of the three pbp genes, pbp2x, pbp2b, and pbp1a in 107, 96, and 88 susceptible and nonsusceptible strains of commensal streptococci, respectively, at the nucleotide and amino acid levels to determine to what extent homologous recombination between commensal streptococci and S. pneumoniae plays a role in the development of beta-lactam resistance in S. pneumoniae. In contrast to pneumococci, extensive sequence variation in the transpeptidase region of pbp2x, pbp2b, and pbp1a was observed in both susceptible and nonsusceptible strains of commensal streptococci, conceivably reflecting the genetic diversity of the many evolutionary lineages of commensal streptococci combined with the recombination events occurring with intra-and interspecies homologues. Our data support the notion that resistance to beta-lactam antibiotics in pneumococci is due to sequences acquired from commensal Mitis group streptococci, especially S. mitis. However, several amino acid alterations previously linked to beta-lactam resistance in pneumococci appear to represent species signatures of the donor strain rather than being causal of resistance.

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“…Thereafter, transformation with two new PBP mutations, in PBP1a and PBP2x, maintained the piperacillin MIC and increased the cefotaxime MIC; remarkably, the transformation also increased the fitness of the triple transformant of S. pneumoniae. In this example, the proteins PBP1a and PBP2x not only showed a complementary function of PBP2b (cell wall maintenance) but also contributed to increasing the resistance to ␤-lactams antibiotics (282).…”

Section: Compensatory Mutationsmentioning

confidence: 95%

“…Albarracín et al (282) have studied an example of this in ␤-lactam-resistant transformants of S. pneumoniae induced by mutations in three penicillin-binding proteins, PBP1a, PBP2x, and PBP2b. Basically, the simple PBP2b mutant used in this study had resistance to piperacillin but also reduced fitness relative to that of the parental strain (measured in both in vitro and in vivo models).…”

Section: Compensatory Mutationsmentioning

confidence: 99%

Antimicrobial Resistance and Virulence: a Successful or Deleterious Association in the Bacterial World?

Beceiro

Tomás²,

Bou³

2013

Clin Microbiol Rev

780

571

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SUMMARY Hosts and bacteria have coevolved over millions of years, during which pathogenic bacteria have modified their virulence mechanisms to adapt to host defense systems. Although the spread of pathogens has been hindered by the discovery and widespread use of antimicrobial agents, antimicrobial resistance has increased globally. The emergence of resistant bacteria has accelerated in recent years, mainly as a result of increased selective pressure. However, although antimicrobial resistance and bacterial virulence have developed on different timescales, they share some common characteristics. This review considers how bacterial virulence and fitness are affected by antibiotic resistance and also how the relationship between virulence and resistance is affected by different genetic mechanisms (e.g., coselection and compensatory mutations) and by the most prevalent global responses. The interplay between these factors and the associated biological costs depend on four main factors: the bacterial species involved, virulence and resistance mechanisms, the ecological niche, and the host. The development of new strategies involving new antimicrobials or nonantimicrobial compounds and of novel diagnostic methods that focus on high-risk clones and rapid tests to detect virulence markers may help to resolve the increasing problem of the association between virulence and resistance, which is becoming more beneficial for pathogenic bacteria.

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Compensatory Evolution of pbp Mutations Restores the Fitness Cost Imposed by β-Lactam Resistance in Streptococcus pneumoniae

Cited by 69 publications

References 44 publications

Pneumococci Can Persistently Colonize Adult Patients with Chronic Respiratory Disease

Pneumococci Can Persistently Colonize Adult Patients with Chronic Respiratory Disease

Commensal Streptococci Serve as a Reservoir for β-Lactam Resistance Genes in Streptococcus pneumoniae

Antimicrobial Resistance and Virulence: a Successful or Deleterious Association in the Bacterial World?

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