Pregnenolone in the treatment of rheumatoid arthritis.

Abstract

<h3>Abstract</h3> <i>Acinetobacter baumannii</i> infection poses a major health threat with recurrent treatment failure due to antibiotic resistance, notably to carbapenems. While genomic analyses of clinical strains indicate that homologous recombination plays a major role in the acquisition of antibiotic resistance genes, the underlying mechanisms of horizontal gene transfer often remain speculative. Our understanding of the acquisition of antibiotic resistance is hampered by the lack of experimental systems able to reproduce genomic observations. We here report the detection of recombination events occurring spontaneously in mixed bacterial populations and which can result in the acquisition of resistance to carbapenems. We show that natural transformation is the main driver of intra-, but also inter-strain recombination events between <i>A. baumannii</i> clinical isolates and pathogenic species of <i>Acinetobacter</i>. We observed that interbacterial natural transformation in mixed populations is more efficient at promoting the acquisition of large resistance islands (AbaR4, AbaR1) than when the same bacteria are supplied with large amounts of purified genomic DNA. Importantly, analysis of the genomes of the recombinant progeny revealed large recombination tracts (from 13 to 123 kb) similar to those observed in the genome of clinical isolates. Moreover, we highlight that transforming DNA availability is a key determinant of the rate of recombinants and results from both spontaneous release and interbacterial predatory behavior. In the light of our results, natural transformation should be considered as a leading mechanism of genome recombination and horizontal gene transfer of antibiotic resistance genes in <i>Acinetobacter baumannii</i>. <h3>Importance</h3> <i>Acinetobacter baumannii</i> is a multidrug resistant pathogen responsible for difficult-to-treat hospital-acquired infections. Understanding the mechanisms leading to the emergence of the multi-drug resistance in this pathogen is today crucial. Horizontal gene transfer is assumed to largely contribute to this multidrug resistance. However, in <i>A. baumannii</i>, the mechanisms leading to genome recombination and the horizontal transfer of resistance genes are poorly understood. We bring experimental evidence that natural transformation, a horizontal gene transfer mechanism recently highlighted in <i>A. baumannii</i>, allows the highly efficient interbacterial transfer of genetic elements carrying resistance to last line antibiotic carbapenems. Importantly, we demonstrated that natural transformation, occurring in mixed populations of <i>Acinetobacter</i>, enables the transfer of large resistance island mobilizing multiple resistance genes.