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SUMMARY:Chemical proteome mining to fight multiresistant bacteria
DTSTART:20200929T092000
DTEND:20200929T180000
DTSTAMP:20260510T165729Z
UID:a2d7a2d4136b43065929c623e043fc6bfe25f9922c1c43d4d4928f15
CATEGORIES:Conferences - Seminars
DESCRIPTION:Prof. Dr. Stephan Sieber \n\nProfessor and Chair of Organic Ch
 emistry II Technical University of Munich\nMultiresistant bacterial pathog
 ens such as Methicillin-resistant Staphylococcus aureus (MRSA) are respons
 ible for a variety of severe infections that pose a significant threat to 
 global health. To approach this challenge new chemical entities with an un
 precedented mode of action are desperately needed. This presentation will 
 cover our latest efforts to identify new anti-bacterial targets and corres
 ponding chemical inhibitors. A proteome mining approach will be presented 
 to identify cofactor-dependent enzymes as novel antibiotic targets. Small 
 molecule cofactor mimics infiltrate the bacterial metabolic machinery lead
 ing to their incorporation in PLP-dependent enzymes. Their analysis via ma
 ss-spectrometry revealed the function of uncharacterized proteins in impor
 tant bacterial pathways as well as the mechanism of action of known antibi
 otics.\nIn a separate approach we identified a new compound class that eff
 ectively kills MRSA strains. Chemical synthesis of improved derivatives le
 d to the identification of an active molecule with nanomolar potency and s
 uitable metabolic stability. Its mode of action was investigated by affini
 ty based protein profiling (AfBPP). The compound stimulates a signal pepti
 dase correlating with enhanced secretion of extracellular proteins. These 
 included essential cell-wall remodeling enzymes whose dysregulation likely
  explains the associated antibiotic effects. Strikingly\, the compound tur
 ned out to be a promising therapeutic candidate as it did not induce in vi
 tro resistance\, exhibited optimal per oral bioavailibility and in vivo ef
 ficacy in a mouse infection model.\n 
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STATUS:CONFIRMED
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