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

Y1 - 2018

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

VL - 152

SP - 370

EP - 376

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

ER -