title: Discovery of new diketopiperazines inhibiting Burkholderia cenocepacia quorum sensing in vitro and in vivo.
abstract: Burkholderia cenocepacia, an opportunistic respiratory pathogen particularly relevant for cystic fibrosis patients, is difficult to eradicate due to its high level of resistance to most clinically relevant antimicrobials. Consequently, the discovery of new antimicrobials as well as molecules capable of inhibiting its virulence is mandatory. In this regard quorum sensing (QS) represents a good target for anti-virulence therapies, as it has been linked to biofilm formation and is important for the production of several virulence factors, including proteases and siderophores. Here, we report the discovery of new diketopiperazine inhibitors of the B. cenocepacia acyl homoserine lactone synthase CepI, and report their anti-virulence properties. Out of ten different compounds assayed against recombinant CepI, four were effective inhibitors, with IC50 values in the micromolar range. The best compounds interfered with protease and siderophore production, as well as with biofilm formation, and showed good in vivo activity in a Caenorhabditis elegans infection model. These molecules were also tested in human cells and showed very low toxicity. Therefore, they could be considered for in vivo combined treatments with established or novel antimicrobials, to improve the current therapeutic strategies against B. cenocepacia.
authors: Dipartimento di Biologia e Biotecnologie, Università degli Studi di Pavia, Via Ferrata, 1-27100 Pavia, Italy.
authors: Viola C
authors: VC
authors: Scoffone
authors: Dipartimento di Biologia e Biotecnologie, Università degli Studi di Pavia, Via Ferrata, 1-27100 Pavia, Italy.
authors: Laurent R
authors: LR
authors: Chiarelli
authors: Lab for Biomedicinal Chemistry, Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, Moscow 119071, Russia.
authors: Vadim
authors: V
authors: Makarov
authors: Lab of Pharmaceutical Microbiology, Ghent University, Ottergemsesteenweg 460, Ghent, 9000, Belgium.
authors: Gilles
authors: G
authors: Brackman
authors: Dipartimento di Biologia e Biotecnologie, Università degli Studi di Pavia, Via Ferrata, 1-27100 Pavia, Italy.|Department of Microbiology, Baku State University, Z. Khalilov 23, AZ1148, Baku, Azerbaijan.
authors: Aygun
authors: A
authors: Israyilova
authors: Neurosurgery, Dipartimento di Scienze Clinico-Chirurgiche e Pediatriche, Università degli Studi di Pavia, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy.|IGM-CNR, Via Abbiategrasso 207, 27100, Pavia, Italy.
authors: Alberto
authors: A
authors: Azzalin
authors: Dipartimento di Biologia e Biotecnologie, Università degli Studi di Pavia, Via Ferrata, 1-27100 Pavia, Italy.
authors: Federico
authors: F
authors: Forneris
authors: Lab for Biomedicinal Chemistry, Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, Moscow 119071, Russia.
authors: Olga
authors: O
authors: Riabova
authors: Lab for Biomedicinal Chemistry, Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, Moscow 119071, Russia.
authors: Svetlana
authors: S
authors: Savina
authors: Lab of Pharmaceutical Microbiology, Ghent University, Ottergemsesteenweg 460, Ghent, 9000, Belgium.
authors: Tom
authors: T
authors: Coenye
authors: Dipartimento di Biologia e Biotecnologie, Università degli Studi di Pavia, Via Ferrata, 1-27100 Pavia, Italy.
authors: Giovanna
authors: G
authors: Riccardi
authors: Dipartimento di Biologia e Biotecnologie, Università degli Studi di Pavia, Via Ferrata, 1-27100 Pavia, Italy.
authors: Silvia
authors: S
authors: Buroni
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects* / Q000254:growth & development; D057508:Burkholderia cenocepacia / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000472:pathogenicity; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000382:microbiology; D002470:Cell Survival / Q000187:drug effects; D003001:Cloning, Molecular; D054659:Diketopiperazines / Q000138:chemical synthesis / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D005822:Genetic Vectors / Q000737:chemistry / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008025:Ligases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D053038:Quorum Sensing / Q000187:drug effects* / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D014774:Virulence
chemical_list: D000900:Anti-Bacterial Agents; D054659:Diketopiperazines; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; C088386:homoserine lactone; D008025:Ligases; C449816:N-acylhomoserine lactone synthase; D015107:4-Butyrolactone