Small-Molecule Inhibitor of
            <i>Vibrio cholerae</i>
            Virulence and Intestinal Colonization

Hung, Deborah T.; Shakhnovich, Elizabeth A.; Pierson, Emily; Mekalanos, John J.

doi:10.1126/science.1116739

Cited by 337 publications

(317 citation statements)

References 19 publications

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“…Remarkably, pilicides do not affect bacterial growth, because pilus production is not essential for bacterial survival and replication. These pilicides represent an example of selective, low-molecular-weight, nonpeptidic virulence-determinant inhibitors (38,39).…”

Section: Resultsmentioning

confidence: 99%

Rationally designed small compounds inhibit pilus biogenesis in uropathogenic bacteria

Pinkner

Remaut

Buelens

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

268

245

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A chemical synthesis platform with broad applications and flexibility was rationally designed to inhibit biogenesis of adhesive pili assembled by the chaperone-usher pathway in Gram-negative pathogens. The activity of a family of bicyclic 2-pyridones, termed pilicides, was evaluated in two different pilus biogenesis systems in uropathogenic Escherichia coli. Hemagglutination mediated by either type 1 or P pili, adherence to bladder cells, and biofilm formation mediated by type 1 pili were all reduced by Ϸ90% in laboratory and clinical E. coli strains. The structure of the pilicide bound to the P pilus chaperone PapD revealed that the pilicide bound to the surface of the chaperone known to interact with the usher, the outer-membrane assembly platform where pili are assembled. Point mutations in the pilicide-binding site dramatically reduced pilus formation but did not block the ability of PapD to bind subunits and mediate their folding. Surface plasmon resonance experiments confirmed that the pilicide interfered with the binding of chaperone-subunit complexes to the usher. These pilicides thus target key virulence factors in pathogenic bacteria and represent a promising proof of concept for developing drugs that function by targeting virulence factors.antimicrobials ͉ chaperone-usher pathway ͉ pilicide ͉ urinary tract infection

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Section: Resultsmentioning

confidence: 99%

Rationally designed small compounds inhibit pilus biogenesis in uropathogenic bacteria

Pinkner

Remaut

Buelens

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

268

245

View full text Add to dashboard Cite

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“…A recent report demonstrated the efficacy of targeting bacterial virulence factors with small molecules for the human pathogen, Vibrio cholerae (33). Unlike traditional antibiotics such as those that inhibit cell wall or protein synthesis, novel ''virulence-specific'' antibiotics would target pathogenic bacteria while sparing commensal bacteria.…”

Section: Resultsmentioning

confidence: 99%

The pathogen-associated iroA gene cluster mediates bacterial evasion of lipocalin 2

Fischbach

Lin

Zhou

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

286

243

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Numerous bacteria cope with the scarcity of iron in their microenvironment by synthesizing small iron-scavenging molecules known as siderophores. Mammals have evolved countermeasures to block siderophore-mediated iron acquisition as part of their innate immune response. Secreted lipocalin 2 (Lcn2) sequesters the Escherichia coli siderophore enterobactin (Ent), preventing E. coli from acquiring iron and protecting mammals from infection by E. coli. Here, we show that the iroA gene cluster, found in many pathogenic strains of Gram-negative enteric bacteria, including E. coli, Salmonella spp., and Klebsiella pneumoniae, allows bacteria to evade sequestration of Ent by Lcn2. We demonstrate that Cglucosylated derivatives of Ent produced by iroA-encoded enzymes do not bind purified Lcn2, and an iroA-harboring strain of E. coli is insensitive to the growth inhibitory effects of Lcn2 in vitro. Furthermore, we show that mice rapidly succumb to infection by an iroA-harboring strain of E. coli but not its wild-type counterpart, and that this increased virulence depends on evasion of host Lcn2. Our findings indicate that the iroA gene cluster allows bacteria to evade this component of the innate immune system, rejuvenating their Ent-mediated iron-acquisition pathway and playing an important role in their virulence.bacterial pathogens ͉ host defense ͉ innate immunity ͉ iron ͉ siderophores

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“…Smallmolecule inhibitors of these transcription factors (Alekshun & Levy, 2005) can be designed to be used alone to prevent infection, or in conjunction with an antibiotic to help treat an infection. A recent study has extended this concept to V. cholerae infection (Hung et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

MarA, SoxS and Rob function as virulence factors in an Escherichia coli murine model of ascending pyelonephritis

et al. 2006

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MarA, SoxS and Rob are transcription factors belonging to the AraC family. While these proteins have been associated historically with control of multiple antibiotic resistance, and tolerance to oxidative stress agents and organic solvents, only a paucity of experimental data support a role in regulating virulence. Clinical Escherichia coli isolates, and isogenic strains lacking marA, soxS and rob, were studied in a murine model of ascending pyelonephritis, which is a clinically relevant model of urinary tract infection. Organisms lacking all three transcription factors (triple knockouts) were significantly less virulent than parental strains, and complementation studies demonstrated that the addition of marA, soxS and rob individually restored wild-type virulence in the triple-knockout strain. Deletion of soxS or rob alone was more detrimental than the removal of marA. Thus, all three proteins contribute to virulence in vivo. INTRODUCTIONThe AraC family of transcription factors is composed of more than 1000 members (Alekshun & Levy, 2004), many of which have well-known roles as virulence factors (Finlay & Falkow, 1997). ExsA from Pseudomonas aeruginosa regulates a type III secretion system (TTSS) (Hauser et al., 1998), Yersinia spp. LcrF (VirF) and YbtA control a TTSS (Flashner et al., 2004) and yersiniabactin (siderophore) (Fetherston et al., 1996) biosynthesis, respectively, and ToxT from Vibrio cholerae governs the synthesis of cholera toxin and toxin coregulated pili (Champion et al., 1997). Inactivation of genes specifying AraC family members [e.g. BfpT, ToxT, LcrF (VirF), Rv1931c, ExsA, Sp1433 and MarA] attenuates virulence in human subjects (Bieber et al., 1998) and a variety of animal infection models (Champion et al., 1997;Flashner et al., 2004; Frota et al., 2004;Hauser et al., 1998;Hava & Camilli, 2002;Randall & Woodward, 2001).Thus, in addition to a primary role in virulence, it is assumed that many members of the AraC family play larger roles in affecting the overall physiology of the bacterial cell.Notably, genomic array experiments have shown that P. aeruginosa ExsA and V. cholerae ToxT regulate the expression of a large collection of genes termed regulons (Bina et al., 2003;Wolfgang et al., 2003).Escherichia coli MarA and SoxS were originally identified based on their ability to control multiple antibiotic resistance (Mar) (George & Levy, 1983a, b), and susceptibility to superoxide and other oxidative stress agents (Wu & Weiss, 1991), respectively. Experiments with Rob, a MarA and SoxS paralogue, showed that it could function in a similar manner (Ariza et al., 1995). Subsequent data have documented multidrug-resistant clinical strains of E. coli (Linde et al., 2000; Maneewannakul & Levy, 1996) and Salmonella enterica serovar Typhimurium (S. typhimurium) (Koutsolioutsou et al., 2001) that constitutively express AraC family members. It is therefore surmised that these proteins may play a role in the infectious process.Although the soxS and mar loci are expressed by S. typhimurium within macrophag...

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Small-Molecule Inhibitor of Vibrio cholerae Virulence and Intestinal Colonization

Cited by 337 publications

References 19 publications

Rationally designed small compounds inhibit pilus biogenesis in uropathogenic bacteria

Rationally designed small compounds inhibit pilus biogenesis in uropathogenic bacteria

The pathogen-associated iroA gene cluster mediates bacterial evasion of lipocalin 2

MarA, SoxS and Rob function as virulence factors in an Escherichia coli murine model of ascending pyelonephritis

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