Bacterial acyl homoserine lactones as immune modulators and drug targets

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DESCRIPTION (provided by applicant): The overarching goal of this research proposal is to investigate the role of bacterial quorum sensing factors in microbial pathogenesis and to then evaluate an anti-virulence strategy based on quorum quenching against selected emerging pathogens, such Acinetobacter baumannii, Yersinia pestis, Burkholderia mallei, and Burkholderia pseudomallei. These Gram-negative bacteria (with the exception of A. baumannii) are category A (Y. pestis) and B (B. pseudomallei and B. mallei) select pathogens, designated so as they are highly likely to be used in incidents of bioterrorism or biowarfare. While not potentially as lethal as other category A and B pathogens, they still pose significant morbidity threats and if delivered by aerosol would have high infectivity potentials. Currently, the number of FDA approved therapies against such bacterial infections is limited to two or three antibiotics and all only have post exposure indications. Additionally, the antibiotic-based therapy could easily be rendered ineffective by introduction of known resistance factors. Therefore, it is of high importance and significance to develop alternative anti-infective strategies for protection against these pathogens. On the other hand, A. baumannii is emerging as a common multi-drug resistance pathogen in nosocomial infections as well as an increasing threat of causing wound infections seen in U.S. soldiers on the battlefields in Iraq and Afghanistan. All pathogens selected for these studies have been shown to utilize bacterial cell-to- cell communication, also called "quorum sensing". Recently, we and others have shown that bacterial QS systems represent an attractive target for prophylactic and therapeutic intervention. QS signaling is based on the exchange of small diffusible molecules, such as N-acyl homoserine lactones (AHL), which are in fact used by A. baumannii, B. mallei, B. pseudomallei and Y. pestis. Similar to classical pathogen-associated molecular patterns (PAMPs), such as bacterial lipopolysaccharide (LPS), and peptidoglycan, AHLs are only produced by microbial pathogens, but not by the mammalian host. Recent research has revealed that the AHL-based QS molecules exert potent cytotoxicity against macrophages, suggesting an additional role for AHLs in dismantling host innate immunity. Studies conducted by the applicants have provided further evidence that AHLs directly activate signaling events in mammalian cells, including leucocytes, and that these occur through mechanisms distinct from the classical PAMP recognition receptor (PRR) pathways, such as the canonical Toll-like receptor (TLR) and Nod-like receptor (NLR) pathways. Therefore, besides their role in bacterial communication, AHL autoinducers themselves might represent new attractive targets for anti-infective immunotherapy. In this proposal, a powerful combination of chemistry, molecular biology, immunology, and genetic approaches will be harnessed to provide a solid rational basis for the generation, development, and evaluation of anti-autoinducer prophylactic and therapeutic strategies. PUBLIC HEALTH RELEVANCE: The bacteria selected for our studies are either new emerging pathogens that have become highly antibiotic resistant, and thus, problematic in clinical settings or are potential bioterrorism and bioware agents. They have been shown to utilize bacterial cell-to-cell communication, also called "quorum sensing" to control their virulence. The molecules that these bacteria use for their communication represent an attractive target for anti-infective therapy as the scavenging of the small compounds would render the bacteria harmless. In addition, these molecules also subvert the host immune system, thus, enabling the microbes to establish their infection in the first place. We propose to develop antibodies for the disruption of bacterial quorum sensing and thus, to develop a new strategy in fighting bacterial infections.