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Role of antibiotics and stress response pathways on virulence and emergence of antibacterial resistance in Straphylococcus aureus

English title Role of antibiotics and stress response pathways on virulence and emergence of antibacterial resistance in Straphylococcus aureus
Applicant Vaudaux Pierre
Number 116518
Funding scheme Project funding
Research institution Service des Maladies Infectieuses Département de Médecine Interne Hôpital Cantonal - HUG
Institution of higher education University of Geneva - GE
Main discipline Experimental Microbiology
Start/End 01.05.2007 - 31.10.2010
Approved amount 296'000.00
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Keywords (9)

Staphylococcus aureus; antimicrobial resistance; ciprofloxacin; SOS DNA repair system; heat shock response pathways; virulence factors; Antibiotic; Bacterial Fitness; DNA Repair Systems

Lay Summary (English)

Lay summary
Staphylococcus aureus are major pathogens of hospital-acquired and community-acquired infections, but also colonize 20-50% of the human population without infectious symptoms. The intensive use of local (antiseptic) or systemic (antibiotics) antimicrobial agents increases the rate of methicillin-resistant S. aureus (MRSA) strains, which become simultaneously resistant to several other, clinically effective antibiotics. Besides promoting the selection of antibiotic-resistant clones, antibiotics may potentially increase resistance to other antibiotic categories by inducing mutations via DNA and protein repair pathways. We evaluated the spectrum of rifampin resistance-conferring mutations in cultures of methicillin-susceptible (MSSA) or methicillin-resistant (MRSA) S. aureus strains exposed in vitro to sub-MICs of ciprofloxacin. Growth of both MSSA and MRSA strains in the presence of sub-MICs of ciprofloxacin led to higher frequencies of rifampin-resistant mutants on rifampin (0.25 µg/mL)-supplemented agar, compared to ciprofloxacin-free conditions. While rifampin-resistant mutants from ciprofloxacin-free cultures essentially showed single amino acid substitutions, a significant proportion of rifampin-resistant mutants from ciprofloxacin-exposed cultures displayed in-frame deletions or insertions in the rpoB gene at several positions of the rifampin resistance cluster I. Frequencies of rifampin-resistant mutants grown in ciprofloxacin-free medium were higher for DNA-repair mutSL mutants compared to their DNA repair-proficient parent. In conclusion, ciprofloxacin-mediated DNA damage in S. aureus, as exemplified by the wide diversity of deletions or insertions in rpoB, suggest the occurrence of major, quinolone-mediated disturbances in DNA fork progression and replication repair. Besides promoting antibiotic resistance, accumulation of unrepaired DNA replication errors, including insertions and deletions, may also contribute to potentially lethal mutations. Another study evaluated the transcriptomic and metabolic responses contributing to S. aureus survival during exposure to supra-physiological temperatures. S. aureus cultures shifted to 48oC, but not 43oC, showed a rapid growth arrest followed by a subsequent decline in viable counts. A relevant metabolic model was designed to explain the combined action of specific stress response mechanisms with more general, energy-regulating metabolic pathways in heat-shocked S. aureus. This model indicates the necessity to down-regulate the production of potential, DNA-damaging reactive oxygen species by excessive levels of free heavy metals, in particular iron.
Direct link to Lay Summary Last update: 21.02.2013

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Associated projects

Number Title Start Funding scheme
103951 Contribution of DNA repair and stress response pathways on virulence and survival of Staphylococcus aureus. 01.05.2004 Project funding