Effective antiprotease-antibiotic treatment of experimental anthrax

<p>Abstract</p> <p>Background</p> <p>Inhalation anthrax is characterized by a systemic spread of the challenge agent, <it>Bacillus anthracis</it>. It causes severe damage, including multiple hemorrhagic lesions, to host tissues and organs. 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 <it>B. anthracis </it>distinct from lethal toxin.</p> <p>Methods</p> <p>Secreted proteins (other than lethal and edema toxins) produced by <it>B. anthracis </it>were tested for tissue-damaging activity and toxicity in mice. Chemical protease inhibitors and rabbit immune sera raised against <it>B. anthracis </it>proteases were used to treat mice challenged with <it>B. anthracis </it>(Sterne) spores.</p> <p>Results</p> <p><it>B. anthracis </it>strain delta Ames (pXO1^-, pXO2^-) 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.</p> <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 <it>B. anthracis</it>, were used to treat mice challenged with <it>B. anthracis </it>(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.</p> <p>Conclusion</p> <p>Secreted proteolytic enzymes are important pathogenic factors of <it>B. anthrasis</it>, which can be considered as effective therapeutic targets in the development of anthrax treatment and prophylactic approaches complementing anti-lethal toxin therapy.</p>

Abstract licence: CC BY-NC-ND

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