TY - JOUR
T1 - Structure-activity-relationship studies of small molecule modulators of the staphylococcal accessory gene regulator
AU - Horswill, Alexander R.
AU - Gordon, Christopher Peter
PY - 2020
Y1 - 2020
N2 - The accessory gene regulator (agr) quorum-sensing system is arguably the most important regulator of Staphylococcus virulence. The agr-system serves a crucial role in pathogenesis by triggering substantive gene expression alterations to upregulate the production of a wide variety of virulence determinants such as exoenzymes (proteases, lipases, nucleases), and downregulate the expression of surface binding proteins. Accordingly, the agr-system represents a compelling target for the development of anti-virulence therapeutics as potential adjuncts, or alternatives, to conventional bactericidal and bacteriostatic antibiotics. Despite this potential, to date, no agr-system inhibitors have progressed to the clinic; however, several promising lead compounds have been identified through screens of synthetic and natural product libraries. Based on the molecular components within the agr-system, the current contingent of regulating compounds can be clustered into three broad groups, AgrA-P3 activation inhibitors, AgrBAgrD processing inhibitors and AgrC-AIP interaction inhibitors. This review aims to provide an overview of the development, structure-activity-relationships, and limitations of compounds within each of these groups in addition to the current opportunities for developing next-generation anologs.
AB - The accessory gene regulator (agr) quorum-sensing system is arguably the most important regulator of Staphylococcus virulence. The agr-system serves a crucial role in pathogenesis by triggering substantive gene expression alterations to upregulate the production of a wide variety of virulence determinants such as exoenzymes (proteases, lipases, nucleases), and downregulate the expression of surface binding proteins. Accordingly, the agr-system represents a compelling target for the development of anti-virulence therapeutics as potential adjuncts, or alternatives, to conventional bactericidal and bacteriostatic antibiotics. Despite this potential, to date, no agr-system inhibitors have progressed to the clinic; however, several promising lead compounds have been identified through screens of synthetic and natural product libraries. Based on the molecular components within the agr-system, the current contingent of regulating compounds can be clustered into three broad groups, AgrA-P3 activation inhibitors, AgrBAgrD processing inhibitors and AgrC-AIP interaction inhibitors. This review aims to provide an overview of the development, structure-activity-relationships, and limitations of compounds within each of these groups in addition to the current opportunities for developing next-generation anologs.
KW - Staphylococcus aureus
KW - extracellular enzymes
KW - genes
UR - http://hdl.handle.net/1959.7/uws:53382
U2 - 10.1021/acs.jmedchem.9b00798
DO - 10.1021/acs.jmedchem.9b00798
M3 - Article
SN - 0022-2623
VL - 63
SP - 2705
EP - 2730
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 6
ER -