Differential Epigenetic Compatibility of qnr Antibiotic Resistance Determinants with the Chromosome of Escherichia coli

Vrije Universiteit Brussel, Belgium
PLoS ONE (Impact Factor: 3.23). 05/2012; 7(5):e35149. DOI: 10.1371/journal.pone.0035149
Source: PubMed


Environmental bacteria harbor a plethora of genes that, upon their horizontal transfer to new hosts, may confer resistance to antibiotics, although the number of such determinants actually acquired by pathogenic bacteria is very low. The founder effect, fitness costs and ecological connectivity all influence the chances of resistance transfer being successful. We examined the importance of these bottlenecks using the family of quinolone resistance determinants Qnr. The results indicate the epigenetic compatibility of a determinant with the host genome to be of great importance in the acquisition and spread of resistance. A plasmid carrying the widely distributed QnrA determinant was stable in Escherichia coli, whereas the SmQnr determinant was unstable despite both proteins having very similar tertiary structures. This indicates that the fitness costs associated with the acquisition of antibiotic resistance may not derive from a non-specific metabolic burden, but from the acquired gene causing specific changes in bacterial metabolic and regulatory networks. The observed stabilization of the plasmid encoding SmQnr by chromosomal mutations, including a mutant lacking the global regulator H-NS, reinforces this idea. Since quinolones are synthetic antibiotics, and since the origin of QnrA is the environmental bacterium Shewanella algae, the role of QnrA in this organism is unlikely to be that of conferring resistance. Its evolution toward this may have occurred through mutations or because of an environmental change (exaptation). The present results indicate that the chromosomally encoded Qnr determinants of S. algae can confer quinolone resistance upon their transfer to E. coli without the need of any further mutation. These results suggest that exaptation is important in the evolution of antibiotic resistance.

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Available from: María B Sánchez
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    • "The Smqnr gene present in the bacterial chromosome contributes to intrinsic quinolones resistance in S. maltophilia.31 Although S. maltophilia isolates harboring Smqnr genes could serve as a reservoir for horizontal transfer of these genes into Enterobacteriaceae, this event is unlikely to occur because plasmids containing Smqnr are unstable.21,32 As the possibility and mechanism for the transfer of levofloxacin resistance gene from other gram-negative bacteria to S. maltophilia have not been fully evaluated, further in vitro study is warranted to verify the association of S. maltophilia with K. pneumoniae with levofloxacin resistance. "
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    ABSTRACT: Purpose Fluoroquinolones, rapidly gaining prominence in treatment of Stenotrophomonas maltophilia (SMP), are noted for their potency and tolerability. However, SMP may rapidly acquire resistance to fluoroquinolones. We evaluated associations of clinical factors with acquisition of levofloxacin resistance (LFr) in SMP. Materials and Methods Our retrospective cohort study was based on patient data collected between January 2008 and June 2010. Through screening of 1275 patients, we identified 122 patients with data for SMP antibiotic susceptibility testing in ≥3 serial SMP isolates. Results We assigned the 122 patients to either the SS group (n=54) in which levofloxacin susceptibility was maintained or the SR group (n=31) in which susceptible SMP acquired resistance. In multivariate regression analysis, exposure to levofloxacin for more than 3 weeks [odds ratio (OR) 15.39, 95% confidential interval (CI) 3.08-76.93, p=0.001] and co-infection or co-colonization with Klebsiella pneumoniae resistant to levofloxacin (OR 4.85, 95% CI 1.16-20.24, p=0.030) were independently associated with LFr acquisition in SMP. Conclusion Acquisition of LFr during serial sampling of SMP was related to the levofloxacin exposure.
    Full-text · Article · Jul 2014 · Yonsei Medical Journal
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    • "At a different hierarchical level, transmission of bacterial cells into secondary hosts (R0), clonal integration of pathogens into host microbiota, and extent of clonal coexistence in the hosts must also be analysed (85). The ‘integration’ of particular genetic elements, and the efficient expression of resistance genes in recipient bacterial cells (49), requires that the overall regulatory and metabolic circuits of the recipient are compatible with the newly incoming elements (21). In fact the ‘lack of integration’ reflects increased fitness costs imposed by the unfit combinations of evolutionary units (see above). "
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    ABSTRACT: Abstract The emergence and spread of antibiotic resistance among human pathogens is a relevant problem for human health and one of the few evolution processes amenable to experimental studies. In the present review, we discuss some basic aspects of antibiotic resistance, including mechanisms of resistance, origin of resistance genes, and bottlenecks that modulate the acquisition and spread of antibiotic resistance among human pathogens. In addition, we analyse several parameters that modulate the evolution landscape of antibiotic resistance. Learning why some resistance mechanisms emerge but do not evolve after a first burst, whereas others can spread over the entire world very rapidly, mimicking a chain reaction, is important for predicting the evolution, and relevance for human health, of a given mechanism of resistance. Because of this, we propose that the emergence and spread of antibiotic resistance can only be understood in a multi-parameter space. Measuring the effect on antibiotic resistance of parameters such as contact rates, transfer rates, integration rates, replication rates, diversification rates, and selection rates, for different genes and organisms, growing under different conditions in distinct ecosystems, will allow for a better prediction of antibiotic resistance and possibilities of focused interventions.
    Full-text · Article · Mar 2014 · Upsala journal of medical sciences
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    • "In the case of antibiotic resistance, it has been discussed that the acquisition of resistance genes can confer a competitive disadvantage (fitness cost) due to the metabolic load required for the replication, transcription and translation of the novel elements acquired by HGT. Recent works indicate that fitness costs can be more specific (Morosini et al., 2000; Sanchez et al., 2002; Alonso et al., 2004; Sanchez and Martinez, 2012) and that the acquisition of novel genes might alter specifically the metabolic bacterial networks (Martinez et al., 2011). In addition, the regulation of the expression of such elements requires to be integrated into the general bacterial regulatory networks (Linares et al., 2010; Martinez and Rojo, 2011). "
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    ABSTRACT: The analysis of the genomes of bacterial pathogens indicates that they have acquired their pathogenic capability by incorporating different genetic elements through horizontal gene transfer. The ancestors of virulent bacteria, as well as the origin of virulence determinants, lay most likely in the environmental microbiota. Studying the role that these determinants may have in non-clinical ecosystems is thus of value for understanding in detail the evolution and the ecology of bacterial pathogens. In this article, I propose that classical virulence determinants might be relevant for basic metabolic processes (for instance iron-uptake systems) or in modulating prey/predator relationships (toxins) in natural, non-infective ecosystems. The different role that horizontal gene transfer and mutation may have in the evolution of bacterial pathogens either for their speciation or in short-sighted evolution processes is also discussed.
    Preview · Article · Jul 2012 · Environmental Microbiology
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