title: Design, synthesis, and a novel application of quorum-sensing agonists as potential drug-delivery vehicles.
abstract: Surface adhered bacterial colonies or biofilms are an important problem in medical and food industries. Bacteria use a chemical language to monitor their quorum and to express virulence factors, which eventually help them in colonization and manifestation of an infection. The LasR-LasI and RhlR-RhlI quorum-sensing (QS) systems of Pseudomonas aeruginosa control expression of virulence factors in a population density-dependent fashion. In this study we investigated the role of synthetic analogs to RhlR-RhlI system of P. aeruginosa strains (PAO-1; wild-type and mutants JP-1, PDO-100, and JP-2) responsible for production of acyl-homoserine lactones-2; butanol homoserine lactone (AHL-2; C(4)-HSL). We synthesized double (QS1207) and single (QS0108) sulfur analogs against (C(4)-HSL; AHL-2), an autoinducer of Pseudomonas QS system. Extensive biological investigation of these analogs suggested a growth promoting activity for these analogs in Pseudomonas controlling biofilm production and exo-protease secretion. We hypothesized that these thiolactone analogs could be potentially utilized as potent drug-delivery vehicles against biofilm-producing pathogens. As a proof of principle we conjugated the single sulfur analog QS0108 with the broad-spectrum antibiotic, ciprofloxacin (QS0108-Cip). The QS analog-antibiotic conjugate was significantly more effective at disrupting both the nascent and mature biofilms of P. aeruginosa than the free antibiotic.
authors.affiliation: Bioscience Division, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
authors.forename: Kumkum
authors.initials: K
authors.lastname: Ganguly
authors.forename: Ruilian
authors.initials: R
authors.lastname: Wu
authors.forename: Morgane
authors.initials: M
authors.lastname: Ollivault-Shiflett
authors.forename: Peter M
authors.initials: PM
authors.lastname: Goodwin
authors.forename: Louis A
authors.initials: LA
authors.lastname: Silks
authors.forename: Rashi
authors.initials: R
authors.lastname: Iyer
mesh_terms: D018441:Biofilms; D016503:Drug Delivery Systems; D013058:Mass Spectrometry; D014677:Pharmaceutical Vehicles; D011550:Pseudomonas aeruginosa / Q000254:growth & development; D011710:Pyocyanine / Q000235:genetics; D053038:Quorum Sensing / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D014677:Pharmaceutical Vehicles; D012333:RNA, Messenger; D011710:Pyocyanine