![]() Furthermore, we found that certain analogs of DSF block its ability to trigger auto-phosphorylation, which coincide with specific alterations in the expression of a subset of P. We demonstrate that two of the five transmembrane helices of the input domain of PA1396 are required for DSF sensing, and DSF binding is associated with enhanced PA1396 auto-phosphorylation. In particular, we focus on the effects of DSF analogs on the PA1396-regulated functions of biofilm formation and antibiotic tolerance, both in vitro and in murine infection models. Here, we examine in more detail the role of PA1396 in sensing DSF family signals and the potential of structural analogs of these signals to modulate PA1396 action. aeruginosa is present together with other bacterial species, suggests interspecies signaling occurs in vivo and may therefore lead to reduced efficacy of antibiotic therapy 13, 14. Detection of DSF family molecules in polybacterial infections, such as those associated with cystic fibrosis (CF) where P. ![]() Deletion of PA1396 in the model strain PAO1 and several clinical isolates also leads to increased tolerance to polymyxins B and E, suggesting DSF negatively modulates PA1396 activity 13, 14. Sensing occurs through the PA1396 histidine kinase and results in altered biofilm formation and increased tolerance to several antibiotics including polymyxin B 13, 14. aeruginosa senses cis-11-methyl-2-dodecenoic acid (DSF) and cis-2-dodecenoic acid (BDSF), which are produced by other bacteria such as Burkholderia species and Stenotrophomonas maltophilia, but not by P. aeruginosa can participate in inter-species signaling mediated by molecules of the diffusible signal factor (DSF) family, which are cis-2-unsaturated fatty acids. In addition to intra-species signaling, P. There are various reports of small molecule inhibition of these pathways with effects on virulence factor synthesis 9, 10, 11. aeruginosa, a widespread opportunistic human pathogen, uses two N-acyl homoserine lactones (3-oxo-dodecanoyl- and butanoyl-HSL) and the quinolone signal PQS (2-heptyl-3-hydroxy-4(1 H)-quinolone) as quorum-sensing molecules that regulate the synthesis of virulence factors 5, 6, 7, 8. ![]() This study addresses the modulation of Pseudomonas aeruginosa by inter-species signaling. Anti-virulence factors are attractive since they do not influence bacterial growth, which may reduce the selective pressure for developing resistance. Bacterial cell–cell communication (quorum sensing), biofilm formation, and cyclic di-GMP signaling were proposed as potential targets for interference by small molecules 1, 2, 3, 4. These strategies include targeting the signaling pathways that regulate the synthesis of microbial virulence factors and approaches to improve the efficacy of existing antibiotics. Similar content being viewed by othersĪntibiotic resistance, coupled with limited development of new antibiotic agents, poses a significant global threat to public health, underscoring the need to find alternative strategies to fight infection 1, 2, 3, 4. These analogues may thus represent lead compounds to develop novel adjuvants improving the efficacy of existing antibiotics. Several of these analogues block the ability of DSF to trigger auto-phosphorylation and gene expression, whereas others act as inverse agonists reducing biofilm formation and antibiotic tolerance, both in vitro and in murine infection models. Further, we examined the ability of synthetic DSF analogues to modulate or inhibit PA1396 activity. DSF binding is associated with enhanced auto-phosphorylation of PA1396 incorporated into liposomes. Here, we show that the membrane-associated sensory input domain of PA1396 has five transmembrane helices, two of which are required for DSF sensing. Sensing these signals leads to altered biofilm formation and increased tolerance to various antibiotics, and requires the histidine kinase PA1396. Pseudomonas aeruginosa, a significant opportunistic pathogen, can participate in inter-species communication through signaling by cis-2-unsaturated fatty acids of the diffusible signal factor (DSF) family.
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