The ubiquitous bacterium Pseudomonas aeruginosa is the quintessential opportunistic pathogen. Certain isolates infect a broad range of host organisms, from plants to humans. The pathogenic promiscuity of particular variants may reflect an increased virulence gene repertoire beyond the core P. aeruginosa genome. We have identified and characterized two P. aeruginosa pathogenicity islands (PAPI-1 and PAPI-2) in the genome of PA14, a highly virulent clinical isolate. The 108-kb PAPI-1 and 11-kb PAPI-2, which are absent from the less virulent reference strain PAO1, exhibit highly modular structures, revealing their complex derivations from a wide array of bacterial species and mobile elements. Most of the genes within these islands that are homologous to known genes occur in other human and plant bacterial pathogens. For example, PAPI-1 carries a complete gene cluster predicted to encode a type IV group B pilus, a well known adhesin absent from strain PAO1. However, >80% of the PAPI-1 DNA sequence is unique, and 75 of its 115 predicted ORF products are unrelated to any known proteins or functional domains. Significantly, many PAPI-1 ORFs also occur in several P. aeruginosa cystic fibrosis isolates. Twenty-three PAPI ORFs were mutated, and 19 were found to be necessary for full plant or animal virulence, with 11 required for both. The large set of ''extra'' virulence functions encoded by both PAPIs may contribute to the increased promiscuity of highly virulent P. aeruginosa strains, by directing additional pathogenic functions.

Long-term antibiotic use generates pan-resistant super pathogens. Anti-infective compounds that selectively disrupt virulence pathways without affecting cell viability may be used to efficiently combat infections caused by these pathogens. A candidate target pathway is quorum sensing (QS), which many bacterial pathogens use to coordinately regulate virulence determinants. The Pseudomonas aeruginosa MvfR-dependent QS regulatory pathway controls the expression of key virulence genes; and is activated via the extracellular signals 4-hydroxy-2-heptylquinoline (HHQ) and 3,4-dihydroxy-2-heptylquinoline (PQS), whose syntheses depend on anthranilic acid (AA), the primary precursor of 4-hydroxy-2-alkylquinolines (HAQs). Here, we identified halogenated AA analogs that specifically inhibited HAQ biosynthesis and disrupted MvfR-dependent gene expression. These compounds restricted P. aeruginosa systemic dissemination and mortality in mice, without perturbing bacterial viability, and inhibited osmoprotection, a widespread bacterial function. These compounds provide a starting point for the design and development of selective anti-infectives that restrict human P. aeruginosa pathogenesis, and possibly other clinically significant pathogens.

Abstract-Case studies and small trials suggest that acupuncture may effectively treat hypertension, but no large randomized trials have been reported. 3 Modalities of complementary and alternative medicine, including acupuncture, are being used by patients with increasing frequency, 4 but these therapies lack demonstrated efficacy and safety for treating cardiovascular disease and hypertension. 5 Acupuncture has been used in traditional Chinese medicine (TCM) to treat symptoms related to hypertension for Ͼ2500 years. 6 Today, acupuncture is commonly used to treat hypertension in China and the West. [7][8][9] The efficacy of acupuncture is well supported for treating postoperative dental pain 10 and nausea 11,12 with few reported adverse effects. 13 Acupuncture has been found effective for treating a number of other acute 14 -16 and chronic 17,18 conditions in a growing number of randomized trials, although opinion differs on the role of placebo effects. 19,20 Mechanistic studies have demonstrated effects of acupuncture on the activity and plasma concentrations of blood pressure modulators, including: renin, aldosterone, angiotensin II, norepinephrine, serotonin, enkephalins, and ␤-endorphins. [21][22][23][24][25][26][27][28][29] The efficacy of acupuncture for treating hypertension is suggested by a large number of published case series and uncontrolled trials. 22,23,25,30 -32 Three randomized trials 33-35 reported significant reductions in BP relative to randomly assigned control groups treated for 4 to 8 weeks, whereas 3 others did not report significant effects of acupuncture relative to control subjects. 36 -38 They were all relatively small trials (nϭ10 to 68), and all but Yin et al 35 were limited