Bacterial Quorum Sensing Modulatory Compounds from Filamentous Fungi as Drugs for Treating Bacterial Infections

Overview

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 Acenitobacter 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 purpose of this project is to develop bacterial quorum sensing inhibitors as a novel class of antibacterial drugs.

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 as stand alone anti-infective drugs or adjuncts to existing antibiotic regimens for treating patients with infections from these bacteria.