Abstract
BackgroundAntibiotic resistance is a major problem for human health. Multidrug resistance efflux pumps, especially those of the Resistance-Nodulation-Cell Division (RND) family, are major contributors to high-level antibiotic resistance in Gram-negative bacteria. Most bacterial genomes contain several copies of the different classes of multidrug resistance efflux pumps. Gene duplication and gain of function by the duplicate copies of multidrug resistance efflux pump genes plays a key role in the expansion and diversification of drug-resistance mechanisms.ResultsWe used two members of the Burkholderia RND superfamily as models to understand how duplication events affect the antibiotic resistance of these strains. First, we analyzed the conservation and distribution of these two RND systems and their regulators across the Burkholderia genus. Through genetic manipulations, we identified both the exact substrate range of these transporters and their eventual interchangeability. We also performed a directed evolution experiment, combined with next generation sequencing, to evaluate the role of antibiotics in the activation of the expression of these systems. Together, our results indicate that the first step to diversify the functions of these pumps arises from changes in their regulation (subfunctionalization) instead of functional mutations. Further, these pumps could rewire their regulation to respond to antibiotics, thus maintaining high genomic plasticity.ConclusionsStudying the regulatory network that controls the expression of the RND pumps will help understand and eventually control the development and expansion of drug resistance.
Highlights
Antibiotic resistance is a major problem for human health
We provide computational and experimental evidence supporting an evolutionary model on the functional diversification of these two Resistance-Nodulation-Cell Division (RND) superfamily members in Burkholderia spp., providing a framework to understand how these events could modulate antibiotic resistance
Comparative genomics and phylogeny The RND 2 operon is located on B. cenocepacia J2315 chromosome 3
Summary
Antibiotic resistance is a major problem for human health. Multidrug resistance efflux pumps, especially those of the Resistance-Nodulation-Cell Division (RND) family, are major contributors to high-level antibiotic resistance in Gram-negative bacteria. Most bacterial genomes contain several copies of the different classes of multidrug resistance efflux pumps. Gene duplication and gain of function by the duplicate copies of multidrug resistance efflux pump genes plays a key role in the expansion and diversification of drug-resistance mechanisms. Multidrug antibiotic resistance (MDR) is a highly attractive model to study the evolution of gene function since hypermutation, complex interrelationships between drug resistance and fitness, compensatory evolution, and epistasis affect how. MDR EP are ancient elements in bacterial genomes, suggesting that their functions predate the resistance to antibiotics during the treatment of human infections [5]. Bacterial genomes often contain multiple copies of different MDR EP classes, which have arisen by gene duplications [6, 7].
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have