The intrinsic resistome of Pseudomonas aeruginosa to β-lactams

Departamento de Biotecnología Microbiana, Centro Nacional de Biotecnología, CSIC, Madrid, Spain.
Virulence (Impact Factor: 4.22). 03/2011; 2(2):144-6. DOI: 10.4161/viru.2.2.15014
Source: PubMed


Pseudomonas aeruginosa is a relevant opportunistic pathogen particularly problematic due to its low intrinsic susceptibility to antibiotics. Intrinsic resistance has been traditionally attributed to the low permeability of cellular envelopes together with the presence of chromosomally-encoded detoxification systems such as multidrug efflux pumps or antibiotic inactivating enzymes. However, some recently published articles indicate that several other elements can contribute to the phenotype of intrinsic resistance of bacterial pathogens. In a recently published article, we explored the chromosomally-encoded determinants that contribute to the phenotype of susceptibility of P. aeruginosa to ceftazidime, imipenem and carbapenem. Using a comprehensive library of transposon-tagged insertion mutants, we found 37 loci in the chromosome of P. aeruginosa that contributed to its intrinsic resistance, because mutants in these loci were more susceptible to antibiotics than their parental strain. 41 further loci could potentially be involved in the acquisition of resistance, because mutants in these loci were less susceptible than their wild-type counterpart. These results indicate that the intrinsic resistome of P. aeruginosa involves several elements, belonging to different functional families and cannot be considered as a specific mechanism of adaptation to the recent usage of antibiotics as therapeutic agents. In the current article, we summarize the findings of the paper and discuss their implications for understanding the evolution of antibiotic resistance and for defining novel targets for the search of new antimicrobials. Finally, the validity of recent theories on the mechanisms of action of antibiotics is discussed taken into consideration the results of our paper and other recently published works on the mechanisms of intrinsic resistance to antibiotics of P. aeruginosa.

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    • "The so-called " intrinsic resistome, " the ensemble of nonacquired genes and functions normally present in bacterial cells which influence the susceptibility to antibiotics, might account for 3% of the bacterial genome (Fajardo et al., 2008). Obviously, such a huge number of " defensive " genes reflects the unspecific nature of their functions in which antibiotic resistance is concerned (Fajardo et al., 2008; Alvarez-Ortega et al., 2011). That does not mean that these genes were not submitted to horizontal gene transfer before the crisis provoked by the industrial antibiotics pollution, illustrating that besides direct selection by clinical antibiotics other factors contribute to dissemination and maintenance of antibiotic resistance genes in bacterial populations (Biel and Hartl, 1983; Aminov and Mackie, 2007; Mindlin et al., 2008; Allen et al., 2009; D'Costa et al., 2011). "
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    ABSTRACT: Antibiotics have natural functions, mostly involving cell-to-cell signaling networks. The anthropogenic production of antibiotics, and its release in the microbiosphere results in a disturbance of these networks, antibiotic resistance tending to preserve its integrity. The cost of such adaptation is the emergence and dissemination of antibiotic resistance genes, and of all genetic and cellular vehicles in which these genes are located. Selection of the combinations of the different evolutionary units (genes, integrons, transposons, plasmids, cells, communities and microbiomes, hosts) is highly asymmetrical. Each unit of selection is a self-interested entity, exploiting the higher hierarchical unit for its own benefit, but in doing so the higher hierarchical unit might acquire critical traits for its spread because of the exploitation of the lower hierarchical unit. This interactive trade-off shapes the population biology of antibiotic resistance, a composed-complex array of the independent "population biologies." Antibiotics modify the abundance and the interactive field of each of these units. Antibiotics increase the number and evolvability of "clinical" antibiotic resistance genes, but probably also many other genes with different primary functions but with a resistance phenotype present in the environmental resistome. Antibiotics influence the abundance, modularity, and spread of integrons, transposons, and plasmids, mostly acting on structures present before the antibiotic era. Antibiotics enrich particular bacterial lineages and clones and contribute to local clonalization processes. Antibiotics amplify particular genetic exchange communities sharing antibiotic resistance genes and platforms within microbiomes. In particular human or animal hosts, the microbiomic composition might facilitate the interactions between evolutionary units involved in antibiotic resistance. The understanding of antibiotic resistance implies expanding our knowledge on multi-level population biology of bacteria. Antibiotics produced by natural organisms play a role in their interactions shaping the lifestyle and homeostasis of bacterial pop-ulations and communities (Waksman, 1961; Davies, 2006; Fajardo and Martínez, 2008; Aminov, 2009). Such interactions might be of antagonistic nature as the production of antibiotics serves to inhibit other bacterial populations. Inhibition does not necessarily intend to kill competitive bacterial organisms, but rather prevent undesirable local overgrowth of partners in shared ecosystems. The diffusion of antibiotics in the environment assures an "exclu-sive zone" at a certain distance from the producer population. At the borders of such a zone, the potentially competing organisms are confronted with very low antibiotic concentrations, proba-bly sufficient to decrease their growth rate, but not to kill the competing neighbor. In this sense, it is highly possible that the production of antagonistic (allelopathic) substances by microor-ganisms has more a defensive than offensive nature (Chao and Levin, 1981). In addition, mutual inhibition is frequently desir-able for the maintenance of healthy species diversity in a particular ecosystem (Czárán et al., 2002; Becker et al., 2012; Cordero et al., 2012). It is of note that natural antibiotic production, decreasing the growth rate of the competing population, not only restricts its local predominance, but also assures that this population is preserved, as antibiotic-promoted cessation of growth is a highly effective system to avoid antibiotic killing. However, the production of natural antibiotics might only have functions unrelated with inter-bacterial antagonisms. Antagonism might arise in particular contexts as a side-effect of cell-to-cell signaling effects resulting in self-regulation of growth, viru-lence, sporulation, motility, mutagenesis, SOS stress response, phage induction, transformation, lateral gene transfer, intra-chromosomal recombination, or biofilm formation (Goh et al., 2002; Ubeda et al., 2005; Linares et al., 2006; Yim et al., 2007; Martínez, 2008; Couce and Blázquez, 2009; Kohanski et al., 2010; Allen et al., 2011; Baharoglu and Mazel, 2011; Pedró et al., 2011; Looft and Allen, 2012; Looft et al., 2012). Natural antibiotic resistance modulates the effect of the natural production of antibiotics, so antibiotic production and antibiotic resistance act as two complementary sides of the same process
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    • "The combination of impermeability and clearance explains why Gram-negative bacteria are inherently more resistant than Gram-positive species, and why new antibiotics active against them are harder to find [3]. Efflux is especially important in Pseudomonas aeruginosa, which has multiple pumps that render it resistant to many drug families active against other Gram-negative species [11,12]. "
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    ABSTRACT: In the 1980s, gram-negative pathogens appeared to have been beaten by oxyimino-cephalosporins, carbapenems, and fluoroquinolones. Yet these pathogens have fought back, aided by their membrane organization, which promotes the exclusion and efflux of antibiotics, and by a remarkable propensity to recruit, transfer, and modify the expression of resistance genes, including those for extended-spectrum β-lactamases (ESBLs), carbapenemases, aminoglycoside-blocking 16S rRNA methylases, and even a quinolone-modifying variant of an aminoglycoside-modifying enzyme. Gram-negative isolates--both fermenters and non-fermenters--susceptible only to colistin and, more variably, fosfomycin and tigecycline, are encountered with increasing frequency, including in Korea. Some ESBLs and carbapenemases have become associated with strains that have great epidemic potential, spreading across countries and continents; examples include Escherichia coli sequence type (ST)131 with CTX-M-15 ESBL and Klebsiella pneumoniae ST258 with KPC carbapenemases. Both of these high-risk lineages have reached Korea. In other cases, notably New Delhi Metallo carbapenemase, the relevant gene is carried by promiscuous plasmids that readily transfer among strains and species. Unless antibiotic stewardship is reinforced, microbiological diagnosis accelerated, and antibiotic development reinvigorated, there is a real prospect that the antibiotic revolution of the 20th century will crumble.
    The Korean Journal of Internal Medicine 06/2012; 27(2):128-42. DOI:10.3904/kjim.2012.27.2.128 · 1.43 Impact Factor
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    ABSTRACT: Within a susceptible wild-type population, a small fraction of cells, even <10(-9) , is not affected when challenged by an antimicrobial agent. This subpopulation has mutations that impede antimicrobial action, allowing their selection during clinical treatment. Emergence of resistance occurs in the frame of a selective compartment termed a mutant selection window (MSW). The lower margin corresponds to the minimum inhibitory concentration of the susceptible cells, whereas the upper boundary, named the mutant prevention concentration (MPC), restricts the growth of the entire population, including that of the resistant mutants. By combining pharmacokinetic/pharmacodynamic concepts and an MPC strategy, the selection of resistant mutants can be limited. Early treatment avoiding an increase of the inoculum size as well as a regimen restricting the time within the MSW can reduce the probability of emergence of the resistant mutants. Physiological and, possibly, genetic adaptation in biofilms and a high proportion of mutator clones that may arise during chronic infections influence the emergence of resistant mutants. Moreover, a resistant population can emerge in a specific selective compartment after acquiring a resistance trait by horizontal gene transfer, but this may also be avoided to some extent when the MPC is reached. Known linkage between antimicrobial use and resistance should encourage actions for the design of antimicrobial treatment regimens that minimize the emergence of resistance. Emergence of a resistant bacterial subpopulation within a susceptible wild-type population can be restricted with a regimen using an antibiotic dose that is sufficiently high to inhibit both susceptible and resistant bacteria.
    FEMS microbiology reviews 07/2011; 35(5):977-91. DOI:10.1111/j.1574-6976.2011.00295.x · 13.24 Impact Factor
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