Antibacterial Agents and Genetics of Resistance
Our group has a long standing interest in unraveling the complexities of bacterial antimicrobial drug resistance.
Bacteria have a remarkable ability to adapt to changes in their environment and this potential for change is dramatically illustrated in the bacterial riposte to antibiotics, antiseptics, disinfectants and heavy metals used in clinical medicine.
Although mutation has an important role to play in the evolution of antibiotic resistance, the predominant factor for the escalation of antibiotic resistance in more than half a century is the acquisition of antibiotic resistance genes.
Data from studies examining this horizontal gene transfer indicate that it is driven by multiple systems that involve both cell to cell transfer and gene transfer from one DNA molecule to another. The latter can take place regardless of the similarity between the donating and recipient molecules and includes systems such as transposons and site-specific recombination systems termed integrons.
Our interests include the study of the class 1 integron system and changes that it has undergone in recent history.
This includes its acquisition by the Tn402/Tn5090 transposon and the subsequent decay of this transposable structure. We are also interested in the new resistance mechanisms that this integration system has recently acquired.
Metallo-b-lactamase encoding genes are one of the most-important of these new resistance mechanisms and our group is at the forefront of research in this area in terms of the discovery of these mechanisms and also their crystallisation and characterisation.
Recently it has become clear that while transposon and integron systems can account for much of the movement of resistance genes between DNA molecules, they fail to explain the spread of a substantial and growing subset of resistance genes.
These resistance genes are linked to sequences termed “common regions”. Our study of these genetic elements has uncovered an extremely powerful gene mobilisation system that we have termed ISCR elements.
These genetic elements are related to the IS91 family of insertion elements and are capable of capturing genes from environmental bacteria and moving them onto the chromosome of pathogens, via transport on promiscuous plasmids.
Analysis of the genetic structures found around these elements also suggests that they are involved in constructing extended multi-drug resistance genetic islands by a combination of replicative transposition and homologous recombination.
ISCR (Insertion Sequence Common Region) elements are Insertion sequences that have similarities to the IS91 family in both structure and function.
These two insertion sequence families have several important features that are unique among IS elements: their terminal sequences are unrelated to each other instead of being inverted repeats; their transposases lack the normal DDE amino acid motif found in the majority of IS elements transposases; they do not generate directly repeated sequence on insertion.
The IS91 family consists of three members IS91, IS801 and IS1294 and the ISCR family currently has 19 members ISCR1-19. Analysis of the genetic loci of the various ISCR elements has revealed that the vast majority of these elements are found in close association with antimicrobial resistance genes that are not the normal complement of the host genome.
They are thus implicated in the acquisition of these genes and appear to have a specialisation for resistance gene transposition.
Structure of individual ISCR elements: