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It is widely believed that anthrax lethal toxin secreted by proliferating bacteria is a major cause of death, however, the pathology of intoxication in experimental animals is drastically different from that found during the infectious process. In order to close a gap between our understanding of anthrax molecular pathology and the most prominent clinical features of the infectious process we undertook bioinformatic and experimental analyses of potential proteolytic virulence factors of<jats:italic>B. anthracis<\/jats:italic>distinct from lethal toxin.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Secreted proteins (other than lethal and edema toxins) produced by<jats:italic>B. anthracis<\/jats:italic>were tested for tissue-damaging activity and toxicity in mice. Chemical protease inhibitors and rabbit immune sera raised against<jats:italic>B. anthracis<\/jats:italic>proteases were used to treat mice challenged with<jats:italic>B. anthracis<\/jats:italic>(Sterne) spores.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:italic>B. anthracis<\/jats:italic>strain delta Ames (pXO1<jats:sup>-<\/jats:sup>, pXO2<jats:sup>-<\/jats:sup>) producing no lethal and edema toxins secrets a number of metalloprotease virulence factors upon cultivation under aerobic conditions, including those with hemorrhagic, caseinolytic and collagenolytic activities, belonging to M4 and M9 thermolysin and bacterial collagenase families, respectively.<\/jats:p><jats:p>These factors are directly toxic to DBA\/2 mice upon intratracheal administration at 0.5 mg\/kg and higher doses. Chemical protease inhibitors (phosphoramidon and 1, 10-phenanthroline), as well as immune sera against M4 and M9 proteases of<jats:italic>B. anthracis<\/jats:italic>, were used to treat mice challenged with<jats:italic>B. anthracis<\/jats:italic>(Sterne) spores. These substances demonstrate a substantial protective efficacy in combination with ciprofloxacin therapy initiated as late as 48 h post spore challenge, compared to the antibiotic alone.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Secreted proteolytic enzymes are important pathogenic factors of<jats:italic>B. anthrasis<\/jats:italic>, which can be considered as effective therapeutic targets in the development of anthrax treatment and prophylactic approaches complementing anti-lethal toxin therapy.<\/jats:p><\/jats:sec>","DOI":"10.1186\/1471-2334-5-25","type":"journal-article","created":{"date-parts":[[2005,4,9]],"date-time":"2005-04-09T06:15:47Z","timestamp":1113027347000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Effective antiprotease-antibiotic treatment of experimental anthrax"],"prefix":"10.1186","volume":"5","author":[{"given":"Serguei G","family":"Popov","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taissia G","family":"Popova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svetlana","family":"Hopkins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond S","family":"Weinstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"MacAfee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl J","family":"Fryxell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikas","family":"Chandhoke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"Bailey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken","family":"Alibek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2005,4,8]]},"reference":[{"key":"173_CR1","doi-asserted-by":"publisher","first-page":"2291","DOI":"10.1073\/pnas.90.6.2291","volume":"90","author":"FA Abramova","year":"1993","unstructured":"Abramova FA, Grinberg LM, Yampolskaya OV, Walker DH: Pathology of inhalational anthrax in 42 cases from the Sverdlovsk outbreak of 1979. 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