Antimicrobials Against the Plague Yersinia bactin System

For over two thousand years Yersinia pestis, the causative agent of bubonic and pneumonic plague, has caused widespread loss of human life during recurrent pandemics. Y. pestis is a category A potential biotemorism agent with natural zoonotic foci as readily available sources of the organism on nearly every continent. The plague bacillus has been used as a biological weapon and weaponized strains were constructed during the Cold War. There is no currently approved vaccine for plague and subunit underdevelopment may not protect humans against wild-type or F1 capsule-negative mutants. Finally, multiple-antibiotic resistant strains of Y. pestis have been isolated from natural sources and could be easily engineered. This proposal willfocus on targeting an essential iron transport system for subunit vaccine development and the identification of alternative antimicrobial agents. The yersiniabactin (Ybt) siderophoredependent iron transport system is essential the early stages of bubonic plague and is important for nature disease progression in pneumonic plague The specific aims of this proposal are to 1) evaluate the outer membrane (OM) receptor for Ybt, termed Psn, as a subunit vaccine candidate; 2) to identify and evaluate alternative antimicrobials that interact with Psn; and 3) to identify and evaluate alternative antimicrobial tht interfere with the synthesis of the Ybt siderophore. The proposed research willdetermine whether Psn is a protective antigen that could be used as part of a subunit vaccine and whether identified antimicrobial compounds that interfere with the Ybt iron transport system can effective cure bubonic and/or pneumonic plague.