ORCID Profile
0000-0002-7941-813X
Current Organisation
University of Oxford
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Publisher: American Society for Microbiology
Date: 31-12-2014
Abstract: Fitness costs play a key role in the evolutionary dynamics of antibiotic resistance in bacteria by generating selection against resistance in the absence of antibiotics. Although the genetic basis of antibiotic resistance is well understood, the precise molecular mechanisms linking the genetic basis of resistance to its fitness cost remain poorly characterized. Here, we examine how the system-wide impacts of mutations in the RNA polymerase (RNAP) gene rpoB shape the fitness cost of rif in resistance in Pseudomonas aeruginosa . Rif in resistance mutations reduce transcriptional efficiency, and this explains 76% of the variation in fitness among rpoB mutants. The pleiotropic consequence of rpoB mutations is that mutants show altered relative transcript levels of essential genes. We find no evidence that global transcriptional responses have an impact on the fitness cost of rif in resistance as revealed by transcriptome sequencing (RNA-Seq). Global changes in the transcriptional profiles of rpoB mutants compared to the transcriptional profile of the rif in-sensitive ancestral strain are subtle, demonstrating that the transcriptional regulatory network of P. aeruginosa is robust to the decreased transcriptional efficiency associated with rpoB mutations. On a smaller scale, we find that rif in resistance mutations increase the expression of RNAP due to decreased termination at an attenuator upstream from rpoB , and we argue that this helps to minimize the cost of rif in resistance by buffering against reduced RNAP activity. In summary, our study shows that it is possible to dissect the molecular mechanisms underpinning variation in the cost of rif in resistance and highlights the importance of genome-wide buffering of relative transcript levels in providing robustness against resistance mutations. IMPORTANCE Antibiotic resistance mutations carry fitness costs. Relative to the characteristics of their antibiotic-sensitive ancestors, resistant mutants show reduced growth rates and competitive abilities. Fitness cost plays an important role in the evolution of antibiotic resistance in the absence of antibiotics however, the molecular mechanisms underlying these fitness costs is not well understood. We applied a systems-level approach to dissect the molecular underpinnings of the fitness costs associated with rif in resistance in P. aeruginosa and showed that most of the variation in fitness cost can be explained by the direct effect of resistance mutations on the enzymatic activity of the mutated gene. Pleiotropic changes in transcriptional profiles are subtle at a genome-wide scale, suggesting that the gene regulatory network of P. aeruginosa is robust in the face of the direct effects of resistance mutations.
Publisher: Springer Science and Business Media LLC
Date: 10-08-2018
Publisher: Springer Science and Business Media LLC
Date: 21-04-2015
DOI: 10.1038/NCOMMS7845
Abstract: Horizontal gene transfer (HGT) plays a key role in bacterial evolution, especially with respect to antibiotic resistance. Fitness costs associated with mobile genetic elements (MGEs) are thought to constrain HGT, but our understanding of these costs remains fragmentary, making it difficult to predict the success of HGT events. Here we use the interaction between P. aeruginosa and a costly plasmid (pNUK73) to investigate the molecular basis of the cost of HGT. Using RNA-Seq, we show that the acquisition of pNUK73 results in a profound alteration of the transcriptional profile of chromosomal genes. Mutations that inactivate two genes encoded on chromosomally integrated MGEs recover these fitness costs and transcriptional changes by decreasing the expression of the pNUK73 replication gene. Our study demonstrates that interactions between MGEs can compromise bacterial fitness via altered gene expression, and we argue that conflicts between mobile elements impose a general constraint on evolution by HGT.
Publisher: The Royal Society
Date: 13-01-2016
Abstract: Antibiotic resistance carries a fitness cost that must be overcome in order for resistance to persist over the long term. Compensatory mutations that recover the functional defects associated with resistance mutations have been argued to play a key role in overcoming the cost of resistance, but compensatory mutations are expected to be rare relative to generally beneficial mutations that increase fitness, irrespective of antibiotic resistance. Given this asymmetry, population genetics theory predicts that populations should adapt by compensatory mutations when the cost of resistance is large, whereas generally beneficial mutations should drive adaptation when the cost of resistance is small. We tested this prediction by determining the genomic mechanisms underpinning adaptation to antibiotic-free conditions in populations of the pathogenic bacterium Pseudomonas aeruginosa that carry costly antibiotic resistance mutations. Whole-genome sequencing revealed that populations founded by high-cost rif icin-resistant mutants adapted via compensatory mutations in three genes of the RNA polymerase core enzyme, whereas populations founded by low-cost mutants adapted by generally beneficial mutations, predominantly in the quorum-sensing transcriptional regulator gene lasR . Even though the importance of compensatory evolution in maintaining resistance has been widely recognized, our study shows that the roles of general adaptation in maintaining resistance should not be underestimated and highlights the need to understand how selection at other sites in the genome influences the dynamics of resistance alleles in clinical settings.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Craig MacLean.