Mechanisms of adaptation to the fitness cost of antibiotic resistance
Author: Paulander, Wilhelm
Date: 2007-06-08
Location: Gard-Aulan, Smittskyddsinstitutet, Nobelsväg 18, Solna
Time: 09.00
Department: Institutionen för mikrobiologi, tumör- och cellbiologi / Department of Microbiology, Tumor and Cell Biology
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Abstract
The dissemination and persistence of antibiotic resistance, is not only
depending on the volume of drugs used but also on the resistance
mechanisms effect of bacterial fitness (reproductive ability). Fitness is
a multifactorial parameter that is comprised of the relative growth rate
of the resistant pathogen in the host and in the environment, as well as
the clearance and transmission rates compared to susceptible strains. The
focus of this thesis has been to determine (i) the connection between the
mechanisms of resistance and their effect on growth in vitro and in a
host-model, and (ii) how different adaptive mechanisms can partly or
fully reverse the deleterious effects of resistance mutations.
More specifically the fitness effect of mutational resistance towards the
translational inhibitors mupirocin and streptomycin, targeting the
isoleucyl–tRNA synthetase (IleRS) and the ribosomal 30S subunit,
respectively were investigated using Salmonella typhimurium as a model
organism. These studies showed that a fitness cost was associated with
the resistance mutations and that suppression of their deleterious effect
could be achieved by both intragenic and extragenic compensatory events.
Three compensatory mechanisms that could restore fitness were identified,
(i) intragenic mutations in the target protein (IleRS), (ii) extragenic
(i.e. outside the target protein) mutations in the ribosomal proteins of
the 30S and 50S subunits and (iii) extragenic compensatory events
increasing the expression of the target protein (IleRS). The mechanism
behind the resistant and compensatory mutations effect on respective
target protein could be determined by in vivo and in vitro kinetical
measurements of ribosomal translation (rate and accuracy) and the IleRS
aminoacylation activity. The impact on activity for the resistant and
compensatory mutations was shown to correlate with their effect on growth
rate. However, since the fitness impact of the resistance mutations has
been seen to vary between different in vitro conditions and between in
vitro and in vivo conditions, we investigated and validated the nematode
Caenorhabditis elegans (C. elegans) as an in vivo model for determining
the fitness effects of resistance against several classes of antibiotics
(including mupirocin and streptomycin). The fitness impact of the
resistance mutations measured in C. elegans, correlated well with what
had been detected in the mouse model of typhoid fever. It is worth noting
that for all resistant strains, relative fitness in the two hostmodels
was lower compared to fitness measured in the Luria Bertani broth
laboratory medium.
In conclusion, we have shown how resistance and compensatory mechanisms
can at the protein and cellular level affect the stability of resistance
in different in vitro and in vivo models.
List of papers:
I. Paulander W, Pennhag A, Andersson DI, Maisnier-Patin S (2007). "Caenorhabditis elegans as a model to determine fitness of antibiotic-resistant Salmonella enterica serovar typhimurium." Antimicrob Agents Chemother 51(2): 766-9. Epub 2006 Nov 20
Pubmed
II. Maisnier-Patin S, Paulander W, Pennhag A, Andersson DI (2007). "Compensatory evolution reveals functional interactions between ribosomal proteins S12, L14 and L19." J Mol Biol 366(1): 207-15. Epub 2006 Nov 15
Pubmed
III. Paulander W, Maisnier-Patin S, Andersson DI (2007). "Multiple mechanisms to ameliorate the fitness burden of mupirocin resistance in Salmonella typhimurium." Mol Microbiol 64(4): 1038-48
Pubmed
I. Paulander W, Pennhag A, Andersson DI, Maisnier-Patin S (2007). "Caenorhabditis elegans as a model to determine fitness of antibiotic-resistant Salmonella enterica serovar typhimurium." Antimicrob Agents Chemother 51(2): 766-9. Epub 2006 Nov 20
Pubmed
II. Maisnier-Patin S, Paulander W, Pennhag A, Andersson DI (2007). "Compensatory evolution reveals functional interactions between ribosomal proteins S12, L14 and L19." J Mol Biol 366(1): 207-15. Epub 2006 Nov 15
Pubmed
III. Paulander W, Maisnier-Patin S, Andersson DI (2007). "Multiple mechanisms to ameliorate the fitness burden of mupirocin resistance in Salmonella typhimurium." Mol Microbiol 64(4): 1038-48
Pubmed
Issue date: 2007-05-18
Rights:
Publication year: 2007
ISBN: 978-91-7357-149-4
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