Diarmaid Hughes
Professor at Department of Medical Biochemistry and Microbiology; Infection and Immunity; Diarmaid Hughes
- Telephone:
- +46 18 471 45 07
- Fax:
- +46 18 471 46 73
- E-mail:
- diarmaid.hughes@imbim.uu.se
- Visiting address:
- BMC
Husargatan 3
752 37 UPPSALA - Postal address:
- Box 582
751 23 UPPSALA
More information is available to staff who log in.
Short presentation
We work on bacterial genetics, evolution of resistance to antibiotics, discovery and development of novel antibiotics, and the evolution of gene order on chromosomes.
If you would like to do a project in my group (for example a masters exam project) please contact me directly by email. I am looking for people with good academic qualifications, interested in problem solving, basic science and bacterial genetics. Note: we are not a clinical microbiology lab. Contact: diarmaid.hughes@imbim.uu.se
Biography
Our main research interests are in bacterial genetics and evolution, including the evolution of antibiotic resistance, the development of novel Gram-negative antibiotics. In studying the evolution of antibiotic resistance, an in-depth understanding of the selection processes and evolutionary principles behind fitness/resistance trade-offs is required for developing methodologies capable of suppressing the growth or spread of resistant bacteria. In this context discovering new drugs or drug targets is very important.
We study the evolution of resistance to antimicrobial drugs, with a particular focus on the fluoroquinolones. Questions include how resistance development impacts on bacterial fitness and how bacteria respond by compensatory evolution.
We are also interested in the organisation of bacterial chromosomes, and how they change through evolution. We have the technology to address fundamental questions experimentally.
If you would like to make a project in my group you should have a good academic record and be interested in logical reasoning and problem solving. Being comfortable with numbers, modelling, computers and data analysis are all advantageous. You should also be prepared to work seriously and hard.
Contact me by email with your CV: diarmaid.hughes@imbim.uu.se
My publication list is on Google Scholar (this is often more up to date than DIVA):
https://scholar.google.com/citations?hl=en&user=rSid04wAAAAJ&pagesize=100&view_op=list_works&sortby=pubdate
Publications
Recent publications
- Discovery and Hit-to-Lead Optimization of Benzothiazole Scaffold- Based DNA Gyrase Inhibitors with Potent Activity against Acinetobacter baumannii and Pseudomonas aeruginosa (2023)
- New Dual Inhibitors of Bacterial Topoisomerases with Broad-Spectrum Antibacterial Activity and In Vivo Efficacy against Vancomycin-Intermediate Staphylococcus aureus (2023)
- Translational in vitro and in vivo PKPD modelling for apramycin against Gram-negative lung pathogens to facilitate prediction of human efficacious dose in pneumonia (2022)
- Expert workshop summary (2022)
- Variability of murine bacterial pneumonia models used to evaluate antimicrobial agents (2022)
All publications
Articles
- Discovery and Hit-to-Lead Optimization of Benzothiazole Scaffold- Based DNA Gyrase Inhibitors with Potent Activity against Acinetobacter baumannii and Pseudomonas aeruginosa (2023)
- New Dual Inhibitors of Bacterial Topoisomerases with Broad-Spectrum Antibacterial Activity and In Vivo Efficacy against Vancomycin-Intermediate Staphylococcus aureus (2023)
- Translational in vitro and in vivo PKPD modelling for apramycin against Gram-negative lung pathogens to facilitate prediction of human efficacious dose in pneumonia (2022)
- Expert workshop summary (2022)
- Variability of murine bacterial pneumonia models used to evaluate antimicrobial agents (2022)
- Evolution of Bacterial Interspecies Hybrids with Enlarged Chromosomes (2022)
- Positive Selection during Niche Adaptation Results in Large-Scale and Irreversible Rearrangement of Chromosomal Gene Order in Bacteria (2022)
- Synthesis and in vitro biological evaluation of quinolinyl pyrimidines targeting type II NADH-dehydrogenase (NDH-2) (2022)
- Genetic Architecture and Fitness of Bacterial Interspecies Hybrids (2021)
- Efficacy of EBL-1003 (apramycin) against Acinetobacter baumannii lung infections in mice (2021)
- Antibacterial activity of apramycin at acidic pH warrants wide therapeutic window in the treatment of complicated urinary tract infections and acute pyelonephritis (2021)
- Antibacterial sulfonimidamide-based oligopeptides as type I signal peptidase inhibitors (2021)
- Evaluating the potential efficacy and limitations of a phage for joint antibiotic and phage therapy of Staphylococcus aureus infections (2021)
- Expression of the qepA1 gene is induced under antibiotic exposure (2021)
- Mutant RNA polymerase can reduce susceptibility to antibiotics via ppGpp-independent induction of a stringent-like response (2021)
- Chromosomal Location Determines the Rate of Intrachromosomal Homologous Recombination in Salmonella (2021)
- ENABLE (2021)
- Resistance/fitness trade-off is a barrier to the evolution of MarR inactivation mutants in Escherichia coli (2021)
- Model-Informed Drug Development for Antimicrobials (2021)
- Phenotypic and genetic barriers to establishment of horizontally transferred genes encoding ribosomal protection proteins (2021)
- The SNAP hypothesis (2020)
- Population Bottlenecks Strongly Influence the Evolutionary Trajectory to Fluoroquinolone Resistance in Escherichia coli (2020)
- Antibiotic resistance by high-level intrinsic suppression of a frameshift mutation in an essential gene (2020)
- Structure-activity relationship studies on the inhibition of the bacterial translation of novel Odilorhabdins analogues (2020)
- Isopedopeptins A-H (2020)
- Synthesis of New N-Acyl-1,2,3-triazole Chalcones and Determination of Their Antibacterial Activity (2020)
- Operon Concatenation Is an Ancient Feature That Restricts the Potential to Rearrange Bacterial Chromosomes (2019)
- Measuring Homologous Recombination Rates between Chromosomal Locations in Salmonella (2019)
- In vitro activity of apramycin against multidrug-, carbapenem- and aminoglycoside-resistant Enterobacteriaceae and Acinetobacter baumannii (2019)
- Co-evolution with recombination affects the stability of mobile genetic element insertions within gene families of Salmonella (2018)
- Mechanisms of fitness cost reduction for rifampicin-resistant strains with deletion or duplication mutations in rpoB. (2018)
- Transcriptional Regulation Buffers Gene Dosage Effects on a Highly Expressed Operon in Salmonella (2018)
- Effect of aminoacyl-tRNA synthetase mutations on susceptibility to ciprofloxacin in Escherichia coli (2018)
- Increased expression of Qnr is sufficient to confer clinical resistance to ciprofloxacin in Escherichia coli (2018)
- Methods to determine mutational trajectories after experimental evolution of antibiotic resistance. (2018)
- Imidazopyrazinones (IPYs) (2018)
- Predicting mutant selection in competition experiments with ciprofloxacin-exposed Escherichia coli (2018)
- Odilorhabdins, Antibacterial Agents that Cause Miscoding by Binding at a New Ribosomal Site (2018)
- Boronic ester-linked macrocyclic lipopeptides as serine protease inhibitors targeting Escherichia coli type I signal peptidase (2018)
- Muramyl Endopeptidase Spr Contributes to Intrinsic Vancomycin Resistance in Salmonella enterica Serovar Typhimurium (2018)
- Selection and Transmission of Antibiotic-Resistant Bacteria (2017)
- Bacterial pathogens, antibiotics and antibiotic resistance (2017)
- Having your cake and eating it - Staphylococcus aureus small colony variants can evolve faster growth rate without losing their antibiotic resistance (2017)
- Alternative Evolutionary Pathways for Drug-Resistant Small Colony Variant Mutants in Staphylococcus aureus (2017)
- Design, synthesis and in vitro biological evaluation of oligopeptides targeting E. coli type I signal peptidase (LepB) (2017)
- Environmental and genetic modulation of the phenotypic expression of antibiotic resistance (2017)
- Evolutionary Trajectories to Antibiotic Resistance (2017)
- Mutation supply and relative fitness shape the genotypes of ciprofloxacin-resistant Escherichia coli (2017)
- Functional Constraints on Replacing an Essential Gene with Its Ancient and Modern Homologs (2017)
- Can a pharmacokinetic/pharmacodynamic (PKPD) model be predictive across bacterial densities and strains? (2017)
- The processive kinetics of gene conversion in bacteria (2017)
- Early-Life Human Microbiota Associated With Childhood Allergy Promotes the T Helper 17 Axis in Mice (2017)
- Ciprofloxacin selects for RNA polymerase mutations with pleiotropic antibiotic resistance effects (2017)
- Fitness cost constrains the spectrum of marR mutations in ciprofloxacin-resistant Escherichia coli (2017)
- Mechanisms and consequences of bacterial resistance to antimicrobial peptides (2016)
- Autoregulation of the tufB operon in Salmonella (2016)
- The Selective Advantage of Synonymous Codon Usage Bias in Salmonella (2016)
- Discovery and structure-activity relationships of a novel isothiazolone class of bacterial type II topoisomerase inhibitors (2016)
- Using the power of genetic suppressors to probe the essential functions of RNase E (2016)
- Evidence for the critical role of a secondary site rpoB mutation in the compensatory evolution and successful transmission of an MDR tuberculosis outbreak strain (2016)
- Comprehensive phenotypic characterization of rifampicin resistance mutations in Salmonella provides insight into the evolution of resistance in Mycobacterium tuberculosis (2015)
- Evolutionary consequences of drug resistance (2015)
- A mechanism-based pharmacokinetic/pharmacodynamic model allows prediction of antibiotic killing from MIC values for WT and mutants (2015)
- Turnover of mRNAs is one of the essential functions of RNase E (2015)
- Genetics (2015)
- Microbiological effects of sublethal levels of antibiotics (2014)
- Reducing ppGpp Level Rescues an Extreme Growth Defect Caused by Mutant EF-Tu (2014)
- Acetate availability and utilization supports the growth of mutant sub-populations on aging bacterial colonies (2014)
- Cell-wall-inhibiting antibiotic combinations with activity against multidrug-resistant Klebsiella pneumoniae and Escherichia coli (2014)
- Selection and Evolution of Resistance to Antimicrobial Drugs (2014)
- Discovery and preclinical development of new antibiotics (2014)
- Mutant prevention concentrations of pradofloxacin for susceptible and mutant strains of Escherichia coli with reduced fluoroquinolone susceptibility (2014)
- Genetic characterization of compensatory evolution in strains carrying rpoB Ser531Leu, the rifampicin resistance mutation most frequently found in clinical isolates (2013)
- Rifampicin Resistance (2013)
- Evolution of antibiotic resistance at non-lethal drug concentrations. (2012)
- Fitness-compensatory mutations in rifampicin-resistant RNA polymerase (2012)
- Selection of resistance at lethal and non-lethal antibiotic concentrations (2012)
- Fitness cost (2012)
- Genome-Wide Detection of Spontaneous Chromosomal Rearrangements in Bacteria (2012)
- Persistence of antibiotic resistance in bacterial populations (2011)
- Selection of Resistant Bacteria at Very Low Antibiotic Concentrations (2011)
- Temperature-sensitive mutants of RNase E in Salmonella enterica (2011)
- Genetic Complexity of Fusidic Acid-Resistant Small Colony Variants (SCV) in Staphylococcus aureus (2011)
- Can phylogenetic type predict resistance development? (2011)
- Can phylogenetic type predict resistance development? (2011)
- Intra- and Extracellular Activities of Dicloxacillin and Linezolid against a Clinical Staphylococcus aureus Strain with a Small-Colony-Variant Phenotype in an In Vitro Model of THP-1 Macrophages and an In Vivo Mouse Peritonitis Model (2011)
- Antibiotic resistance and its cost (2010)
- Biological roles of translesion synthesis DNA polymerases in eubacteria (2010)
- Effect of the translesion DNA polymerases, endonucleases and RpoS on mutation rates in Salmonella typhimurium (2010)
- Gene amplification and adaptive evolution in bacteria (2009)
- Genetic Determinants of Resistance to Fusidic Acid among Clinical Bacteremia Isolates of Staphylococcus aureus (2009)
- Interplay in the Selection of Fluoroquinolone Resistance and Bacterial Fitness (2009)
- Mutants of the RNA-processing enzyme RNase E reverse the extreme slow-growth phenotype caused by a mutant translation factor EF-Tu (2008)
- Identification of the Genetic Basis for Clinical Menadione-Auxotrophic Small-Colony Variant Isolates of Staphylococcus aureus (2008)
- Accumulation of mutants in "aging" bacterial colonies is due to growth under selection, not stress-induced mutagenesis (2008)
- Genetic and phenotypic identification of fusidic acid-resistant mutants with the small-colony-variant phenotype in Staphylococcus aureus (2007)
- Dose-related selection of fluoroquinolone-resistant Escherichia coli (2007)
- Selection of ciprofloxacin resistance in Escherichia coli in an in vitro kinetic model (2006)
- Weak mutators can drive the evolution of fluoroquinolone resistance in Escherichia coli (2006)
- Biological cost of single and multiple norfloxacin resistance mutations in Escherichia coli implicated in urinary tract infections (2005)
- Establishment of a superficial skin infection model in mice by using Staphylococcus aureus and Streptococcus pyogenes (2005)
- Hyper-susceptibility of a fusidic acid-resistant mutant of Salmonella to different classes of antibiotics (2005)
- Mutant prevention concentrations of ciprofloxacin for urinary tract infection isolates of Escherichia coli (2005)
- Evidence against reciprocal recombination as the basis for tuf gene conversion in Salmonella enterica serovar Typhimurium (2004)
- Fusidic acid-resistant mutants of Salmonella enterica serovar typhimurium have low levels of heme and a reduced rate of respiration and are sensitive to oxidative stress (2004)
- Exploiting genomics, genetics and chemistry to combat antibiotic resistance (2003)
- Mutation Rate and Evolution of Fluoroquinolone Resistance in Escherichia coli Isolates from Patients with Urinary tract infections (2003)
- Fusidic acid-resistant mutants of Salmonella enterica serovar Typhimurium with low fitness in vivo are defective in RpoS induction (2003)
- The physiological cost of antibiotic resistance (2003)
- Biological cost and compensatory evolution in fusidic acid-resistant Staphylococcus aureus (2001)
- Effects of environment on compensatory mutations to ameliorate costs of antibiotic resistance (2000)
- Co-evolution of the tuf genes links gene conversion with the generation of chromosomal inversions (2000)
- Evaluating genome dynamics: the constraints on rearrangements within bacterial genomes (2000)
- Structure of a mutant EF-G reveals domain III and possibly the fusidic acid binding site (2000)
- Fusidic acid-resistant EF-G perturbs the accumulation of ppGpp (2000)
- Novel ribosomal mutations affecting translational accuracy, antibiotic resistance and virulence of Salmonella typhimurium (1999)
- Antibiotikaresistens: är den reversibel? (1998)
- Antibiotikaresistens här för att stanna? (1998)
- Virulence of antibiotic-resistant Salmonella typhimurium (1998)
- Carbon starvation of Salmonella typhimurium does not cause a general increase of mutation rates (1997)
- Mutants of EF-Tu defective in binding aminoacyl-tRNA (1996)
- Homologous recombination between the tuf genes of Salmonella typhimurium (1996)
- Muller's ratchet decreases fitness of a DNA-based microbe (1996)
- The dynamic structure of EF-G studied by fusidic acid resistance and internal revertants (1996)
- tRNA-ribosome interactions (1995)
- A new mutation in 16S rRNA of Escherichia coli conferring spectinomycin resistance (1995)
- Mutations to kirromycin resistance occur in the interface of domains I and III of EF-Tu.GTP (1994)
- Fusidic acid-resistant mutants define three regions in elongation factor G of Salmonella typhimurium (1994)
- Ternary complex-ribosome interaction: its influence on protein synthesis and on growth rate (1993)
- A single amino acid substitution in elongation factor Tu disrupts interaction between the ternary complex and the ribosome (1993)
- Growth and translation elongation rate are sensitive to the concentration of EF-Tu (1993)
- Suppression of rpsL phenotypes by tuf mutations reveals a unique relationship between translation elongation and growth rate (1993)
- Comparison of the complete sequence of the str operon in Salmonella typhimurium and Escherichia coli (1992)
- Missense substitutions lethal to essential functions of EF-Tu (1991)
- Error-prone EF-Tu reduces in vivo enzyme activity and cellular growth rate (1991)
- The nucleotide sequence of rpsL and its flanking regions in Salmonella typhimurium (1991)
- Mutant ribosomes can generate dominant kirromycin resistance (1991)
- Both genes for EF-Tu in Salmonella typhimurium are individually dispensible for growth (1990)
- Overproduction of release factor reduces spontaneous frameshifting and frameshift suppression by mutant elongation factor Tu (1990)
- The role of EF-Tu and other translation components in determining translocation step size (1990)
- Design, synthesis, and in vitro biological evaluation of meta-sulfonamidobenzamide-based antibacterial LpxH inhibitors
- A large chromosomal inversion causes the formation of an unstable tufA/B hybrid operon
- Co-evolution protects the tuf genes from inactivation by mobile genetic elements
- High-level intrinsic suppression of a frameshift mutation in an essential gene
- Quantifying combined effects of colistin and ciprofloxacin against Escherichia coli in an in silico pharmacokinetic-pharmacodynamic model
Books
Chapters
- Elongation Factors (2017)
- The origin of mutants under selection (2010)
- Adventures with mutation and selection in beehive and cow country (2010)
- Measurements of heme levels and respiration rate in Salmonella enterica serovar typhimurium (2010)
- Assays of sensitivity of antibiotic-resistant bacteria to hydrogen peroxide and measurement of catalase activity (2010)
- Effects of antibiotic resistance on bacterial fitness, virulence and transmission (2008)
- Comparative genomics and the development of novel antimicrobials (2008)
- Biological consequences for bacteria of homologous recombination (2005)
- Target alterations mediating antibiotic resistance (2001)
- Impact of homologous recombination and gene conversion on genomic organisation and stability (1999)
- Limitations of translational accuracy (1996)
