TY - JOUR
T1 - Lactam hybrid analogues of solonamide B and autoinducing peptides as potent S. aureus AgrC antagonists
AU - Hansen, Anna Mette
AU - Peng, Pai
AU - Baldry, Mara
AU - Perez-Gassol, Iris
AU - Christensen, Simon B.
AU - Vinther, Joachim Møllesøe
AU - Ingmer, Hanne
AU - Franzyk, Henrik
N1 - Copyright © 2018 Elsevier Masson SAS. All rights reserved.
PY - 2018/5/25
Y1 - 2018/5/25
N2 - Emergence of antibiotic-resistant bacteria constitutes an increasing threat to human health. For example, treatment options for Staphylococcus aureus infections is declining with the worldwide spreading of highly virulent community-associated methicillin-resistant S. aureus (CA-MRSA) strains. Anti-virulence therapy has been proposed as an alternative treatment strategy, as it typically involves inhibition of expression of virulence factors rather than direct bacterial killing, thereby attenuating the risk of resistance development. An intriguing target is the agr quorum-sensing system, which is a major inducer of virulence in CA-MRSA upon activation by agr-encoded staphylococcal autoinducing peptides (AIPs). In the present work a previously identified lactam hybrid analogue based on the marine depsipeptide solonamide B and the general structure of AIPs was investigated with respect to structure-function relationships. An array of 27 analogues exploring expansion of ring size, type of side chain, amino acid substitutions, and stereochemistry was designed and tested for AgrC-inhibitory activity. Interestingly, it was found that an analogue derived from the mirror image of the original hit proved to be the hitherto most efficient AgrC inhibitor resembling solonamide B in amino acid sequence. This and closely related compounds were 20- to 40-fold more potent in AgrC inhibition than the starting hit compound.
AB - Emergence of antibiotic-resistant bacteria constitutes an increasing threat to human health. For example, treatment options for Staphylococcus aureus infections is declining with the worldwide spreading of highly virulent community-associated methicillin-resistant S. aureus (CA-MRSA) strains. Anti-virulence therapy has been proposed as an alternative treatment strategy, as it typically involves inhibition of expression of virulence factors rather than direct bacterial killing, thereby attenuating the risk of resistance development. An intriguing target is the agr quorum-sensing system, which is a major inducer of virulence in CA-MRSA upon activation by agr-encoded staphylococcal autoinducing peptides (AIPs). In the present work a previously identified lactam hybrid analogue based on the marine depsipeptide solonamide B and the general structure of AIPs was investigated with respect to structure-function relationships. An array of 27 analogues exploring expansion of ring size, type of side chain, amino acid substitutions, and stereochemistry was designed and tested for AgrC-inhibitory activity. Interestingly, it was found that an analogue derived from the mirror image of the original hit proved to be the hitherto most efficient AgrC inhibitor resembling solonamide B in amino acid sequence. This and closely related compounds were 20- to 40-fold more potent in AgrC inhibition than the starting hit compound.
KW - Bacterial Proteins/antagonists & inhibitors
KW - Dose-Response Relationship, Drug
KW - Lactams/chemistry
KW - Molecular Conformation
KW - Peptides, Cyclic/chemical synthesis
KW - Protein Kinase Inhibitors/chemical synthesis
KW - Protein Kinases/metabolism
KW - Structure-Activity Relationship
KW - beta-Lactamases/metabolism
U2 - 10.1016/j.ejmech.2018.04.053
DO - 10.1016/j.ejmech.2018.04.053
M3 - Journal article
C2 - 29738955
SN - 0223-5234
VL - 152
SP - 370
EP - 376
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
ER -
