Many bacterial pathogens posses a cell-to-cell signaling pathway termed quorum sensing (QS). In these bacteria the QS pathway regulates population-wide behaviors and responses such a biofilm formation and induction of a repertoire of virulence essential genes. Examples of such bacteria include Burkholderia pseudomallei, which causes a severe disease call melioidosis, Pseudomonas aeruginosa, a frequent agent of pulmonary colonization and acute pneumonias in cystic fibrosis patients, and Acinetobacter baumannii, an emerging agent of nosocomial infections. These organisms inhabit environmental niches and exhibit high levels of native resistance to multiple classes of antibiotics. The soil environment constitutes a very complex ecological niche occupied by numerous species including bacteria and fungi. The organisms occupying this niche are competing with each other for nutrients, water, and other factors essential for reproduction and survival. Within this niche, some bacteria and filamentous fungi deploy a diverse array of bioactive compounds, termed natural products or secondary metabolites, to mediate their competitive interactions with their niche neighbors, competitors, and predators. It is from this chemical weapons armamentarium that 50-75% of our newly approved drugs are either obtained directly or that served as lead compound for synthesis of derivatives that are ultimately approved for human therapeutic use. Secondary metabolite inhibitors and activators of bacterial quorum sensing appears to have evolved in the filamentous fungi. These QS modulatory compounds were undoubtedly evolved to thwart whatever competitive advantage these QS systems provide to the bacteria relative to the fungi in this environment. We have designed, validated, and employed, an assay to detect bacterial quorum sensing inhibitory activity in secondary metabolite extracts prepared from Aspergillus and Penicillium fungi. We have found such activity to be widely present in these fungi. Several publications support the use of such inhibitors as therapeutic interventions in managing the infections by such QS regulated pathogenic bacteria. As noted, these bacteria typically exhibit high native levels of antibiotic drug resistance. Our hypothesis is that QS inhibitory drugs will be effective standalone anti-infective drugs or adjuncts to existing antibiotic regimens for treating patients with infections from these bacteria. We propose to continue our efforts in this study to develop bacterial quorum sensing inhibitors as a novel class of antibacterial drugs.
Many severe bacterial infections are caused by organisms that regulate their ability to cause disease through a control system call quorum sensing (QS). These QS systems evolved through competition in their normal soil environment to provide the bacteria with a competitive advantage over filamentous fungi and other organisms including the fungi that share the same soil environment. In response to the challenge by QS regulating bacteria, many of these fungi developed chemical weapons that disrupt the bacterial quorum sensing systems. The proposed project will develop these fungi produced chemicals as a novel class of drugs. These drugs will disrupt the bacterial QS regulatory system when it operates to allow the bacteria to infect human patients. This QS disruption will make it easier for traditional antibiotics to kill the bacteria and clear the infection. Many of these bacteria have a natural high resistance to traditional antibiotics and these new drugs will provide an important additional means for treating these serious and persistent infections.
