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Factors favouring the evolution of multidrug resistance in bacteria

ABSTRACT: The evolution of multidrug antibiotic resistance in commensal bacteria is an important public health concern. Commensal bacteria such as Escherichia coli, Streptococcus pneumoniae or Staphylococcus aureus, are also opportunistic pathogens causing a large fraction of the community-acquired and hospital-acquired bacterial infections. Multidrug resistance (MDR) makes these infections harder to treat with antibiotics and may thus cause substantial additional morbidity and mortality. Here, we develop an evolutionary epidemiology model to identify the factors favouring the evolution of MDR in commensal bacteria. The model describes the evolution of antibiotic resistance in a commensal bacterial species evolving in a host population subjected to multiple antibiotic treatments. We combine statistical analysis of a large number of simulations and mathematical analysis to understand the model behaviour. We find that MDR evolves more readily when it is less costly than expected from the combinations of single resistances (positive epistasis). MDR frequently evolves when bacteria are in contact with multiple drugs prescribed in the host population, even if individual hosts are only treated with a single drug at a time. MDR is favoured when the host population is structured in different classes that vary in their rates of antibiotic treatment. However, under most circumstances, recombination between loci involved in resistance does not meaningfully affect the equilibrium frequency of MDR. Together, these results suggest that MDR is a frequent evolutionary outcome in commensal bacteria that encounter the variety of antibiotics prescribed in the host population. A better characterization of the variability in antibiotic use across the host population (e.g. across age classes or geographical location) would help predict which MDR genotypes will most readily evolve.

SUBMITTER: Jacopin E

PROVIDER: S-EPMC7423433 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Project description:BackgroundMembers of the small multidrug resistance (SMR) protein family are integral membrane proteins characterized by four alpha-helical transmembrane strands that confer resistance to a broad range of antiseptics and lipophilic quaternary ammonium compounds (QAC) in bacteria. Due to their short length and broad substrate profile, SMR proteins are suggested to be the progenitors for larger alpha-helical transporters such as the major facilitator superfamily (MFS) and drug/metabolite transporter (DMT) superfamily. To explore their evolutionary association with larger multidrug transporters, an extensive bioinformatics analysis of SMR sequences (> 300 Bacteria taxa) was performed to expand upon previous evolutionary studies of the SMR protein family and its origins.ResultsA thorough annotation of unidentified/putative SMR sequences was performed placing sequences into each of the three SMR protein subclass designations, namely small multidrug proteins (SMP), suppressor of groEL mutations (SUG), and paired small multidrug resistance (PSMR) using protein alignments and phylogenetic analysis. Examination of SMR subclass distribution within Bacteria and Archaea taxa identified specific Bacterial classes that uniquely encode for particular SMR subclass members. The extent of selective pressure acting upon each SMR subclass was determined by calculating the rate of synonymous to non-synonymous nucleotide substitutions using Syn-SCAN analysis. SUG and SMP subclasses are maintained under moderate selection pressure in comparison to integron and plasmid encoded SMR homologues. Conversely, PSMR sequences are maintained under lower levels of selection pressure, where one of the two PSMR pairs diverges in sequence more rapidly than the other. SMR genomic loci surveys identified potential SMR efflux substrates based on its gene association to putative operons that encode for genes regulating amino acid biogenesis and QAC-like metabolites. SMR subclass protein transmembrane domain alignments to Bacterial/Archaeal transporters (BAT), DMT, and MFS sequences supports SMR participation in multidrug transport evolution by identifying common TM domains.ConclusionBased on this study, PSMR sequences originated recently within both SUG and SMP clades through gene duplication events and it appears that SMR members may be evolving towards specific metabolite transport.

Project description:Obesity is a major global health problem and predisposes individuals to several comorbidities that can affect life expectancy. Interventions based on lifestyle modification (for example, improved diet and exercise) are integral components in the management of obesity. However, although weight loss can be achieved through dietary restriction and/or increased physical activity, over the long term many individuals regain weight. The aim of this article is to review the research into the processes and mechanisms that underpin weight regain after weight loss and comment on future strategies to address them. Maintenance of body weight is regulated by the interaction of a number of processes, encompassing homoeostatic, environmental and behavioural factors. In homoeostatic regulation, the hypothalamus has a central role in integrating signals regarding food intake, energy balance and body weight, while an 'obesogenic' environment and behavioural patterns exert effects on the amount and type of food intake and physical activity. The roles of other environmental factors are also now being considered, including sleep debt and iatrogenic effects of medications, many of which warrant further investigation. Unfortunately, physiological adaptations to weight loss favour weight regain. These changes include perturbations in the levels of circulating appetite-related hormones and energy homoeostasis, in addition to alterations in nutrient metabolism and subjective appetite. To maintain weight loss, individuals must adhere to behaviours that counteract physiological adaptations and other factors favouring weight regain. It is difficult to overcome physiology with behaviour. Weight loss medications and surgery change the physiology of body weight regulation and are the best chance for long-term success. An increased understanding of the physiology of weight loss and regain will underpin the development of future strategies to support overweight and obese individuals in their efforts to achieve and maintain weight loss.

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Factors favouring the evolution of multidrug resistance in bacteria

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