title: Virulence-targeted Antibacterials: Concept, Promise, and Susceptibility to Resistance Mechanisms.
abstract: In view of the relentless increase in antibiotic resistance in human pathogens, efforts are needed to safeguard our future therapeutic options against infectious diseases. In addition to regulatory changes in our antibiotic use, this will have to include the development of new therapeutic compounds. One area that has received growing attention in recent years is the possibility to treat or prevent infections by targeting the virulence mechanisms that render bacteria pathogenic. Antivirulence targets include bacterial adherence, secretion of toxic effector molecules, bacterial persistence through biofilm formation, quorum sensing and immune evasion. Effective small-molecule compounds have already been identified that suppress such processes. In this review, we discuss the susceptibility of such compounds to the development of resistance, by comparison with known resistance mechanisms observed for classical bacteriostatic or bacteriolytic antibiotics, and by review of available experimental case studies. Unfortunately, appearance of resistance mechanisms has already been demonstrated for some, showing that the quest of new, lasting drugs remains complicated.
authors.affiliation: Structural and Molecular Microbiology, Structural Biology Research Center, VIB, Pleinlaan 2, Brussels, 1050, Belgium.|Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, Brussels, 1050, Belgium.
authors.forename: Ségolène
authors.initials: S
authors.lastname: Ruer
authors.affiliation: Institute of Structural and Molecular Biology (ISMB), UCL and Birkbeck College, London, WC1E 7HX, UK.
authors.forename: Nikos
authors.initials: N
authors.lastname: Pinotsis
authors.affiliation: Wolfson Institute for Biomedical Research (WIBR), UCL, London, WC1E 6BT, UK.
authors.forename: David
authors.initials: D
authors.lastname: Steadman
authors.affiliation: Institute of Structural and Molecular Biology (ISMB), UCL and Birkbeck College, London, WC1E 7HX, UK.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Waksman
authors.affiliation: Structural and Molecular Microbiology, Structural Biology Research Center, VIB, Pleinlaan 2, Brussels, 1050, Belgium.|Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, Brussels, 1050, Belgium.
authors.forename: Han
authors.initials: H
authors.lastname: Remaut
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000627:therapeutic use; D001419:Bacteria / Q000378:metabolism / Q000472:pathogenicity*; D001422:Bacterial Adhesion / Q000187:drug effects; D001424:Bacterial Infections / Q000188:drug therapy* / Q000378:metabolism; D018441:Biofilms / Q000187:drug effects* / Q000254:growth & development; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D006801:Humans; D053038:Quorum Sensing / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents
keywords: antibiotic resistance; bacterial virulence; drug discovery; mechanism-based drug design; molecular recognition; therapeutic target