Combinatorial genetic evolution of multiresistance
Introduction
The increasing escalation of antibiotic resistance, particularly in Gram-negative pathogens such as Pseudomonas aeruginosa, Acinetobacter baumannii and Escherichia coli, has prompted calls for numerous interventions; not least, curtailing antibiotic usage, improved infection control policies and antimicrobial development programs. With respect to the first of these, the gene pool might already be firmly established and, besides, the procurement and expression of new genetic material, even antibiotic resistant genes might be influenced by other factors other than antibiotic challenge. In this field of study we observe interesting but unexplainable trends; that is, why are certain genotypes like blaCTX--15 and blaCMY-2 so successful? Or why is blaVIM-2 found in P. aeruginosa, yet blaVIM-1 is found predominantly in Enterobacteriaceae? The dominance of a single genetic entity or ‘piece’ (gene or series of genes) appears to be more influenced by its surrounding DNA than the gene itself, either by facilitating rapid mobilisation and/or encoding other functions, for example enhanced survival or fitness [1].
The explosion in genetic databases in the past 10 years has increased our knowledge — if not our understanding — of antibiotic resistance. Notwithstanding, it is becoming increasingly apparent that the gene pool is larger than we had previously considered, and so is the ‘tool kit’ used to mediate the mobility of such entities [1, 2, 3••]. Moreover, as imported DNA within a bacterium grows both in size and diversity, the higher the probability of further additional DNA being procured through homologous recombination, and so the DNA evolves — in perpetuum.
It could be argued that the importation and construction of these genetic entities might be serendipitous; however, it is more likely to be driven by ‘forces’, accommodating not only its importation but also its subsequent rearrangement and maintenance [1, 3••]. Irrespective of the genetic revolution, there still exists very little information on these forces and whether they act in a co-ordinated or destructive fashion. For example, the ‘success’ of plasmid transfer is more likely to do with the promiscuity of the host strain than the plasmid backbone or the resistance, virulence or fitness genes carried on it and thus more conjugation studies involving wild type isolates are needed [4]. A recent study supports this notion in which the E. coli genome was systematically reduced (by up to 15.3%) through precise deletions, and this resulted in counter-intuitive findings: the altered strain (K12) exhibited accurate propagation of recombinant genes and plasmids that are not stable in other strains [5]. The association of extended spectrum β-lactamases (ESBLs) in E. coli with increased mutations poses similar questions on the role of the host in acquiring foreign genetic entities [1].
Using examples primarily pertaining to antibiotic resistance, this review provides an update on how entities are mobilised, examines genetic construction (and deconstruction), and explores some of these forces that facilitate their dissemination.
Section snippets
Trojan horses and antibiotic resistance
The term Trojan horse has been applied to many biological ‘packages’, such as mobile DNA and viruses, that at first appear straightforward, but result in being more complex and even destructive. The term could also apply to bacterial plasmids and the accompanying mobile elements, possibly representing the guileful Odysseus. However, the destruction of the recipient rarely occurs — unlike in the fate of Troy! Nonetheless, the translocation of DNA from the plasmid to the chromosome can be readily
DNA arrangement: favouring the imprecise?
Recent studies involving ‘genetic slippage’ have shed new light on how genetic entities, such as blaCTX-M, can be duplicated and mobilised. The elegant studies of Poirel et al. [15••, 16] demonstrated the mobilisation of blaCTX--15 by ISEcp1B (belonging to the IS1380 family) and concluded that normally only ISEcp1B would be mobilised, because the transposition event would be terminated at the cognate inverted repeat (IRR) [15••]. However, because of the infidelity of ISEcpB1, the IRR was often
ISCRs: the latest variation on mobility?
Recently, a new type of genetic element, the common region (CR or ISCR), has been identified as being closely associated with the spread of many antibiotic resistance genes [18•, 19•]. Generally, they can be divided into two groups: those that form complex class 1 integrons (termed ISCR1) and those that are associated with non-class 1 integrons (ISCR2–12 at the time of writing this article) [18•, 19•]. ISCRs are increasingly associated with mega-antibiotic resistance regions. ISCR1 (or open
Entities within entities: integrons, transposons and insertion elements
Our understanding of the arrangement of bacterial genetics continues to be challenged with increasing combinations and permutations of a variety of genetic entities. Even those entities that are only associated with antibiotic resistance are increasingly appearing more complex. Arguably the smallest mobile genetic entity encoding antibiotic resistance are gene cassettes carried on integrons, particularly class 1 integrons. These can encode many types of resistance including to trimethoprim,
Forces altering genetic diversity
It has long been argued that the key driver of antibiotic resistance is antibiotic consumption, and that the use of antibiotics has spawned the advent of the ‘Superbug’ — a perfect example of Darwinian selection! However, such conclusions can be argued as being parsimonious and do not always reflect the broader picture on the acquisition of genetic entities, their maintenance and forces that might influence this. [4]. For example, several individual Salmonella environmental isolates without
Conclusion
To fully understand antibiotic resistance we must enhance our knowledge of gene flow and what factors influences these dynamics. For example, blaCTX- genes that are naturally found in Kluyvera species, have probably spread from the community or general practice into hospitals rather than vice versa [15••, 16]. However, once established the gene pool might concentrate within hospitals and ultimately be recycled through hospital waste back into the community — and so the cycle continues and will
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
I would like to thank Dr Mark A Toleman for his critique and comments on the manuscript.
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