| 1. |
- Cars, Otto, et al.
(författare)
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Resetting the agenda for antibiotic resistance through a health systems perspective
- 2021
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Ingår i: The Lancet Global Health. - : Elsevier. - 2214-109X. ; 9:7, s. E1022-E1027
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Forskningsöversikt (refereegranskat)abstract
- Although the individual and societal consequences of antibiotic resistance spiral upwards, coordinated action has not kept pace on a global scale. The COVID-19 pandemic has highlighted the need for resilient health systems and has resulted in an unprecedented rate of collaboration in scientific, medical, social, and political dimensions. The pandemic has also created a renewed awareness of the importance of infectious diseases and is a substantial entry point for reigniting the momentum towards containing the silent pandemic of antibiotic resistance. In this Viewpoint, we discuss the limitations in the current narrative on antibiotic resistance and how it could be improved, including concerted efforts to close essential data gaps. We discuss the need for capacity building and coordination at the national and global levels to strengthen the understanding of the importance of sustainable access to effective antibiotics for all health systems that could generate tangible links to current processes for global health and development.
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| 2. |
- Pavlov, Michael, et al.
(författare)
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Initiation factor 2 mutants promoting fast joining of ribosomal subunits in the absence of initiator tRNA or GTP
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- We have previously identified several mutations in initiation factor 2 (IF2) located outside the tRNA binding domain IV of IF2 that compensate for lack of initiator tRNA (Met-tRNAi) formylation in vivo. We have also shown that these IF2 mutants promote fast joining of ribosomal subunits even when non-formylated Met-tRNAi or deacylated tRNAi was present in the 30S pre-initiation complex (30S PIC) instead of formylated fMet-tRNAi. We demonstrate here in vitro that these IF2 mutants do not require any tRNA present on the 30S subunit to promote fast subunit joining provided that GTP is present. Moreover, in the presence of fMet-tRNAi the mutants promote fast subunit joining in the presence of only GDP. Thus, A-type IF2 mutants require either GTP or fMet-tRNAi for fast subunit joining. In contrast, fast subunit joining with wild type IF2 requires the presence of both GTP and fMet-tRNAi in the 30S PIC. These results imply that the presence of tRNA on the 30S subunit is per se not required for fast subunit joining but rather for switching the 30S:IF2 complex containing wild type IF2 into its 50S docking conformation. We show also that the rate of subunit joining with A-type IF2 is much less sensitive to the energy level in the reaction mixture than the rate of subunit joining with wild type IF2. We speculate that this insensitivity of initiation to energy levels may result in deteriorated adaptation of formylation-proficient strains harbouring A-type mutations in IF2 to growth under energy-limited conditions.
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| 3. |
- Søgaard Jørgensen, Peter, et al.
(författare)
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Coevolutionary Governance of Antibiotic and Pesticide Resistance
- 2020
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Ingår i: Trends in Ecology & Evolution. - : Elsevier BV. - 0169-5347 .- 1872-8383. ; 35:6, s. 484-494
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Forskningsöversikt (refereegranskat)abstract
- Development of new biocides has dominated human responses to evolution of antibiotic and pesticide resistance. Increasing and uniform biocide use, the spread of resistance genes, and the lack of new classes of compounds indicate the importance of navigating toward more sustainable coevolutionary dynamics between human culture and species that evolve resistance. To inform this challenge, we introduce the concept of coevolutionary governance and propose three priorities for its implementation: (i) new norms and mental models for lowering use, (ii) diversifying practices to reduce directional selection, and (iii) investment in collective action institutions to govern connectivity. We highlight the availability of solutions that facilitate broader sustainable development, which for antibiotic resistance include improved sanitation and hygiene, strong health systems, and decreased meat consumption.
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| 4. |
- Zorzet, Anna, 1977-, et al.
(författare)
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Compensatory evolution restores fitness to actinonin-resistant Staphylococcus aureus
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- We have studied the emergence of actinonin-resistant mutants in S. aureus. In accordance with earlier studies we identified resistance mutations in the fmt gene that apart from conferring high-level resistance also reduced the growth rate. To study how fitness could be restored we performed compensatory evolution by serial passage of cells in liquid culture. Compensated mutants arose quickly, within 40 generations and sometimes in less than 10 generations. The mutants were fully resistant to actinonin and showed increased growth rates on plates. However, exponential growth rates in liquid media were not higher than for the parental resistant mutants. We sequenced the whole genomes of one slow-growing strain and three compensated and found alterations in three genes. These genes were SAOUHSC_01699 coding for shikimate 5-dehydrogenase, SAOUHSC_00945 coding for a magnesium transporter and SAOUHSC_02264, coding for accessory gene regulator protein C (AgrC). None of these mutants were obvious candidates for compensating lack of formylation. When sequencing these three loci in the remainder of the compensated strains, mutations in agrC were found in 11 of 16 strains. Further studies will show if these mutations are due to general environmental adaption, specific adaptation for slow growth or specific compensation for loss of formylation.
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| 5. |
- Zorzet, Anna, 1977-, et al.
(författare)
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Error-prone initiation factor 2 mutations reduce the fitness cost of antibiotic resistance
- 2010
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Ingår i: Molecular Microbiology. - : Wiley-Blackwell. - 0950-382X .- 1365-2958. ; 75:5, s. 1299-1313
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in the fmt gene (encoding formyl methionine transferase) that eliminate formylation of initiator tRNA (Met-tRNA(i)) confer resistance to the novel antibiotic class of peptide deformylase inhibitors (PDFIs) while concomitantly reducing bacterial fitness. Here we show in Salmonella typhimurium that novel mutations in initiation factor 2 (IF2) located outside the initiator tRNA binding domain can partly restore fitness of fmt mutants without loss of antibiotic resistance. Analysis of initiation of protein synthesis in vitro showed that with non-formylated Met-tRNA(i) IF2 mutants initiated much faster than wild-type IF2, whereas with formylated fMet-tRNA(i) the initiation rates were similar. Moreover, the increase in initiation rates with Met-tRNA(i) conferred by IF2 mutations in vitro correlated well with the increase in growth rate conferred by the same mutations in vivo, suggesting that the mutations in IF2 compensate formylation deficiency by increasing the rate of in vivo initiation with Met-tRNA(i). IF2 mutants had also a high propensity for erroneous initiation with elongator tRNAs in vitro, which could account for their reduced fitness in vivo in a formylation-proficient strain. More generally, our results suggest that bacterial protein synthesis is mRNA-limited and that compensatory mutations in IF2 could increase the persistence of PDFI-resistant bacteria in clinical settings.
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| 6. |
- Zorzet, Anna, 1977-
(författare)
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Mechanisms of Adaptation to Deformylase Inhibitors
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Antibiotic resistance is a growing problem on a global scale. Increasing numbers of bacteria resistant toward one or multiple antibiotics could return us to the high mortality rates for infectious diseases of the pre-antibiotic era. The need for development of new classes of antibiotics is great as is increased understanding of the mechanisms underlying the development of antibiotic resistance. We have investigated the emergence of resistance to peptide deformylase inhibitors, a new class of antibiotics that target bacterial protein synthesis. The fitness of resistant mutants as well as their propensity to acquire secondary compensatory mutations was assessed in order to gain some insight into the potential clinical risk of resistance development. Most of this work was done in the bacterium Salmonella typhimurium, due to the availability of excellent genetic tools to study these phenomena. In addition, we have studied the bacterium Staphylococcus aureus as peptide deformylase inhibitors have been shown to have the greatest effect on Gram-positive organisms. In the course of this work we also examined the mechanistic aspects of translation initiation. Using a cell-free in vitro translation system we studied the effects of various components on translation initiation. These results have been combined with results obtained from resistant and compensated bacterial strains in vivo to gain new insights into the mechanisms of translation initiation.
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