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Antiinfective therapy with a small molecule inhibitor of Staphylococcus aureus sortase
- Source :
- Proceedings of the National Academy of Sciences of the United States of America, Proceedings of the National Academy of Sciences of the United States of America, National Academy of Sciences, 2014, 111 (37), pp.13517-13522. ⟨10.1073/pnas.1408601111⟩, Proceedings of the National Academy of Sciences of the United States of America, 2014, 111 (37), pp.13517-13522. ⟨10.1073/pnas.1408601111⟩
- Publication Year :
- 2014
- Publisher :
- HAL CCSD, 2014.
-
Abstract
- International audience; Methicillin-resistant Staphylococcus aureus (MRSA) is the most frequent cause of hospital-acquired infection, which manifests as surgical site infections, bacteremia, and sepsis. Due to drug-resistance, prophylaxis of MRSA infection with antibiotics frequently fails or incites nosocomial diseases such as Clostridium difficile infection. Sortase A is a transpeptidase that anchors surface proteins in the envelope of S. aureus, and sortase mutants are unable to cause bacteremia or sepsis in mice. Here we used virtual screening and optimization of inhibitor structure to identify 3-(4-pyridinyl)-6-(2-sodiumsulfonatephenyl)[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole and related compounds, which block sortase activity in vitro and in vivo. Sortase inhibitors do not affect in vitro staphylococcal growth yet protect mice against lethal S. aureus bacteremia. Thus, sortase inhibitors may be useful as antiinfective therapy to prevent hospital-acquired S. aureus infection in high-risk patients without the side effects of antibiotics.
- Subjects :
- Models, Molecular
[SDV]Life Sciences [q-bio]
Antibiotics
medicine.disease_cause
computational screening
Anti-Infective Agents
Sortase
MESH: Staphylococcus aureus
antivirulence
MESH: Animals
MESH: Bacterial Proteins
0303 health sciences
Mice, Inbred BALB C
MESH: Microbial Sensitivity Tests
Multidisciplinary
MESH: Protease Inhibitors
MESH: Peptides
Clostridium difficile
Biological Sciences
Aminoacyltransferases
3. Good health
Cysteine Endopeptidases
Staphylococcus aureus
Sortase A
nosocomial infection
Female
MESH: Streptococcus pyogenes
MESH: Biocatalysis
MESH: Models, Molecular
medicine.drug_class
Streptococcus pyogenes
MESH: Anti-Infective Agents
MESH: Mice, Inbred BALB C
Microbial Sensitivity Tests
MESH: Thiadiazoles
Biology
LPXTG motif
Microbiology
Sepsis
Small Molecule Libraries
03 medical and health sciences
Bacterial Proteins
MESH: Small Molecule Libraries
MESH: Aminoacyltransferases
Thiadiazoles
medicine
Animals
Protease Inhibitors
030304 developmental biology
030306 microbiology
medicine.disease
Virology
Bacteremia
Biocatalysis
Peptides
MESH: Female
MESH: Cysteine Endopeptidases
Subjects
Details
- Language :
- English
- ISSN :
- 00278424 and 10916490
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America, Proceedings of the National Academy of Sciences of the United States of America, National Academy of Sciences, 2014, 111 (37), pp.13517-13522. ⟨10.1073/pnas.1408601111⟩, Proceedings of the National Academy of Sciences of the United States of America, 2014, 111 (37), pp.13517-13522. ⟨10.1073/pnas.1408601111⟩
- Accession number :
- edsair.doi.dedup.....53070f7025ad6711cdeb65c5216b6782