Role of insertion sequences in the control of antibiotic resistance in acinetobacter baumannii

Abstract

Acinetobacter baumannii is an emerging multiresistant pathogen increasingly known to cause infections in the immuno-compromised patients. Carbapenems and colistin are considered to be the last resorts in treatment of infections involving multidrug resistant strains of A. baumannii. Resistance to carbapenems is well known due to the presence of intrinsic carbapenemase gene blaOXA-51-like, which may be governed by insertion elements, or by acquired carbapenemases like blaOXA-23-like, blaOXA-58-like or blaOXA-40-like genes, most of which are frequently associated with insertion elements. The acquired carbapenemases can be integrated with the host chromosome making the bacterium strongly resistant to a range of antibiotics. Recent reports also suggest that the ubiquitous and intrinsic enzymes encoded by the blaOXA-51-like gene can be mobilized on a plasmid. In this thesis, the prevalence of antibiotic resistance was examined for 96 strains isolated from various parts of the world. The resistances to aminoglycosides, fluoroquinolones and cephalosporins were studied with a major focus on resistance to carbapenems. Section 1 shows the transposition of ISAba1 and its varied influence in controlling the blaOXA-51-like gene and the blaADC gene. It explains how ISAba1 being a strong factor in influencing antibiotic resistance genes contributes to the plasticity of the organism Section 2 is related with a novel insertion element ISAba125 controlling the blaADC gene and as an element providing high resistance to ceftazidime in comparison to ISAba1. Section 3 analyses the multi-drug resistant profile of strains isolated from Cochabamba, Bolivia. Besides the classification of carbapenem resistance for the clinical strains, the aminoglycoside resistance and ciprofloxacin mechanisms are examined in this project Section 4 relates with the pattern of resistance in strains isolated from the Aberdeen Royal Infirmary. It describes two novel variants of the blaOXA-51-like gene, namely blaOXA-216 and blaOXA-217 and also the acquisition of the blaOXA-23-like gene in two isolates from different years and deemed identical by their PFGE pattern. Section 5 describes the influence of ISAba825 in controlling the blaOXA-51-like gene and the blaOXA-58-like from clinical isolates Section 6 is related with the insertional inactivation of the blaOXA-132 gene and the carbapenem resistance caused by the activation of the blaOXA-58 gene in isolate Ab244 Section 7 describes the influence of insertion elements in strains having high ciprofloxacin resistance. This project is concerned with the role of efflux pump control system adeRS and how they influence the adeABC operon causing increased and decreased expression of the genes. Section 8 describes the multi drug resistant pattern of 36 strains each isolated from Europe and the United States In conclusion, there are various factors that influence the resistance profile of multidrug resistant A. baumannii isolates with insertion sequences such as ISAba1, ISAba2, ISAba3, ISAba825, IS1008, ISAba125, ISAba16 governing the expression or providing alternate mechanisms of resistance for the better fitness of the bacterium. Mutations in the genes identified in this study also have a crucial role in imparting resistance to this bacterium.