PMID- 30770405 OWN - NLM STAT- MEDLINE DCOM- 20200323 LR - 20200323 IS - 1098-5336 (Electronic) IS - 0099-2240 (Print) IS - 0099-2240 (Linking) VI - 85 IP - 8 DP - 2019 Apr 15 TI - Disruption of Quorum Sensing and Virulence in Burkholderia cenocepacia by a Structural Analogue of the cis-2-Dodecenoic Acid Signal. LID - 10.1128/AEM.00105-19 [doi] LID - e00105-19 AB - Quorum sensing (QS) signals are widely used by bacterial pathogens to control biological functions and virulence in response to changes in cell population densities. Burkholderia cenocepacia employs a molecular mechanism in which the cis-2-dodecenoic acid (named Burkholderiadiffusible signal factor [BDSF]) QS system regulates N-acyl homoserine lactone (AHL) signal production and virulence by modulating intracellular levels of cyclic diguanosine monophosphate (c-di-GMP). Thus, inhibition of BDSF signaling may offer a non-antibiotic-based therapeutic strategy against BDSF-regulated bacterial infections. In this study, we report the synthesis of small-molecule mimics of the BDSF signal and evaluate their ability to inhibit BDSF QS signaling in B. cenocepacia A novel structural analogue of BDSF, 14-Me-C(16:Delta2) (cis-14-methylpentadec-2-enoic acid), was observed to inhibit BDSF production and impair BDSF-regulated phenotypes in B. cenocepacia, including motility, biofilm formation, and virulence, while it did not inhibit the growth rate of this pathogen. 14-Me-C(16:Delta2) also reduced AHL signal production. Genetic and biochemical analyses showed that 14-Me-C(16:Delta2) inhibited the production of the BDSF and AHL signals by decreasing the expression of their synthase-encoding genes. Notably, 14-Me-C(16:Delta2) attenuated BDSF-regulated phenotypes in various Burkholderia species. These findings suggest that 14-Me-C(16:Delta2) could potentially be developed as a new therapeutic agent against pathogenic Burkholderia species by interfering with their QS signaling.IMPORTANCEBurkholderia cenocepacia is an important opportunistic pathogen which can cause life-threatening infections in susceptible individuals, particularly in cystic fibrosis and immunocompromised patients. It usually employs two types of quorum sensing (QS) systems, including the cis-2-dodecenoic acid (BDSF) system and N-acyl homoserine lactone (AHL) system, to regulate virulence. In this study, we have designed and identified an unsaturated fatty acid compound (cis-14-methylpentadec-2-enoic acid [14-Me-C(16:Delta2)]) that is capable of interfering with B. cenocepacia QS signaling and virulence. We demonstrate that 14-Me-C(16:Delta2) reduced BDSF and AHL signal production in B. cenocepacia It also impaired QS-regulated phenotypes in various Burkholderia species. These results suggest that 14-Me-C(16:Delta2) could interfere with QS signaling in many Burkholderia species and might be developed as a new antibacterial agent. CI - Copyright (c) 2019 American Society for Microbiology. FAU - Cui, Chaoyu AU - Cui C AD - School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou, China. AD - Integrative Microbiology Research Centre, College of Agriculture, South China Agricultural University, Guangzhou, China. FAU - Song, Shihao AU - Song S AD - School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou, China. AD - Integrative Microbiology Research Centre, College of Agriculture, South China Agricultural University, Guangzhou, China. FAU - Yang, Chunxi AU - Yang C AD - School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou, China. AD - Integrative Microbiology Research Centre, College of Agriculture, South China Agricultural University, Guangzhou, China. FAU - Sun, Xiuyun AU - Sun X AD - School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou, China. AD - Integrative Microbiology Research Centre, College of Agriculture, South China Agricultural University, Guangzhou, China. FAU - Huang, Yutong AU - Huang Y AD - Integrative Microbiology Research Centre, College of Agriculture, South China Agricultural University, Guangzhou, China. FAU - Li, Kang AU - Li K AD - Integrative Microbiology Research Centre, College of Agriculture, South China Agricultural University, Guangzhou, China. FAU - Zhao, Shuo AU - Zhao S AD - Integrative Microbiology Research Centre, College of Agriculture, South China Agricultural University, Guangzhou, China. FAU - Zhang, Yongliang AU - Zhang Y AD - Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. FAU - Deng, Yinyue AU - Deng Y AD - School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou, China yinyue_deng@hotmail.com. AD - Integrative Microbiology Research Centre, College of Agriculture, South China Agricultural University, Guangzhou, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190404 PL - United States TA - Appl Environ Microbiol JT - Applied and environmental microbiology JID - 7605801 RN - 0 (2-dodecenoic acid) RN - 0 (Acyl-Butyrolactones) RN - 0 (Bacterial Proteins) RN - 0 (Fatty Acids, Monounsaturated) RN - 61093-23-0 (bis(3',5')-cyclic diguanylic acid) RN - H2D2X058MU (Cyclic GMP) SB - IM MH - Acyl-Butyrolactones/metabolism MH - Bacterial Proteins/genetics/metabolism MH - Biofilms/drug effects MH - Burkholderia Infections/microbiology/prevention & control MH - Burkholderia cenocepacia/*drug effects/genetics/metabolism MH - Cyclic GMP/analogs & derivatives/metabolism MH - Fatty Acids, Monounsaturated/*antagonists & inhibitors/*pharmacology MH - Gene Expression Regulation, Bacterial MH - Microbial Sensitivity Tests MH - Phenotype MH - Quorum Sensing/*drug effects MH - Signal Transduction MH - Virulence/drug effects/genetics PMC - PMC6450033 OTO - NOTNLM OT - AHL OT - BDSF OT - Burkholderia cenocepacia OT - quorum sensing OT - virulence EDAT- 2019/02/17 06:00 MHDA- 2020/03/24 06:00 PMCR- 2019/10/04 CRDT- 2019/02/17 06:00 PHST- 2019/01/13 00:00 [received] PHST- 2019/02/07 00:00 [accepted] PHST- 2019/02/17 06:00 [pubmed] PHST- 2020/03/24 06:00 [medline] PHST- 2019/02/17 06:00 [entrez] PHST- 2019/10/04 00:00 [pmc-release] AID - AEM.00105-19 [pii] AID - 00105-19 [pii] AID - 10.1128/AEM.00105-19 [doi] PST - epublish SO - Appl Environ Microbiol. 2019 Apr 4;85(8):e00105-19. doi: 10.1128/AEM.00105-19. Print 2019 Apr 15.