Antiinfective therapy with a small molecule inhibitor of Staphylococcus aureus sortase.
Jie Zhang,Hongchuan Liu,Kongkai Zhu,Shouzhe Gong,Shaynoor Dramsi,Ya-Ting Wang,Jiafei Li,Feifei Chen,Ruihan Zhang,Lu Zhou,Lefu Lan,Hualiang Jiang,Olaf Schneewind,Cheng Luo,Cai-Guang Yang +14 more
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TLDR
Virtual screening and optimization of inhibitor structure is used to identify 3,6-disubstituted triazolothiadiazole compounds as inhibitors of sortase, an enzyme that incorporates surface proteins into the staphylococcal envelope that may prevent hospital-acquired S. aureus infection in high-risk patients without the side effects of antibiotics.Abstract:
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.read more
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Cell Density Control of Staphylococcal Virulence Mediated by an Octapeptide Pheromone
TL;DR: This study has demonstrated that the synthesis of Staphylococcus aureus virulence factors is controlled by a density-sensing system that utilizes an octapeptide produced by the organism itself.
Journal ArticleDOI
Different drugs for bad bugs: antivirulence strategies in the age of antibiotic resistance
TL;DR: The theory behind antivirulence strategies is outlined, the recent successes and failures of this paradigm, and new developments that are in the pipeline are discussed.
Journal ArticleDOI
Prevention and treatment of Staphylococcus aureus biofilms
TL;DR: Two broad anti-infective strategies are discussed: preventative approaches (anti-biofilm surface coatings, the inclusion of biofilm-specific vaccine antigens); and approaches aimed at eradicating established S. aureus biofilms, particularly those associated with implant infections.
Journal ArticleDOI
Bacterial proteases, untapped antimicrobial drug targets.
TL;DR: The potential for and recent progress in the development of compounds targeting bacterial proteases with a focus on AAA+ family proteolytic complexes and signal peptidases are described, offering an arsenal of novel antibiotic targets ripe for development.
Book ChapterDOI
Anti-virulence Strategies to Target Bacterial Infections.
Sabrina Mühlen,Petra Dersch +1 more
TL;DR: This chapter takes a closer look at the bacterial virulence-related factors and processes that present promising targets for anti-virulence therapies, recently discovered inhibitory substances and their promises and discusses the challenges, and problems that have to be faced.
References
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TL;DR: The molecular epidemiology of the epidemic waves of peniillin- and methicillin-resistant strains of S. aureus that have occurred since 1940 are reviewed, with a focus on the clinical and molecular epidemiological of CA-MRSA.
Journal ArticleDOI
Surface Proteins of Gram-Positive Bacteria and Mechanisms of Their Targeting to the Cell Wall Envelope
TL;DR: The mechanisms for both sorting and targeting of proteins to the envelope of gram-positive bacteria are described and the functions of known surface proteins are reviewed.