Yersinia pestis is the infectious agent of bubonic plague, however it can also cause pneumonic and septicemic plague. All three forms have been responsible for high mortality rates in epidemics throughout human history, including the "black death" that accounted for the death of approximately one-third of the European population during the Middle Ages. Nowadays, Yersinia pestis is still considered a rather serious "Critical Biological Agent" as it could be used against the military or civilian populations as a bioweapon. Given the availability of Y. pestis around the world, capacity for its mass production and aerosol dissemination, difficulty in preventing such activities, high fatality rate of the different forms of plague, and potential for secondary spread of cases during an epidemic, the potential use of plague as a biological weapon is of great concern. Yersinae use a number of toxins to evade the immune system one of which is the protein tyrosine phosphatase YopH. Injected into phagocytic cell types via the bacterial type III sectretion system, YopH is a highly active bacterial PTPase that is results in disruption of focal adhesions, and inhibition of integrin-mediated bacterial phagocytosis, both of which are highly dependent on tyrosine phosphorylation. The non-selective PTP inhibitor orthovanadate impairs the anti-phagocytic effect of wild-type strains or Yersinia, demonstrating the importance of bacteria-derived YopH activity for this event. Hence, small-molecule inhibitors of YopH would be expected to render YopH-paralyzed immune cells immediately functional again to initiate both innate and adaptive immune responses. We anticipate that these inhibitors would be most effective in the early stages of infection where the amount of YopH produced and injected by Yersiniae is relatively low, but it is conceivable that YopH inhibitors could still be efficient at later stages of infection where the disease otherwise is invariably lethal. Moreover, in addition to serve as potential novel therapeutic compounds, the molecules that will arise from this study may result very useful in probing at the cellular level the mechanisms of toxin induced cell death and inhibition of phagocytosis, which is common to several other pathogens. Hence, our developed series of inhibitors and relative data will serve as general resource for to the scientific community outside the scope of the current application, supporting efforts on understanding how Yersinia pestis, Salmonella enterica, Francisella tularensis, Chlamydia psiticai, and Strep. Pneumonia, for example, modulate innate immunity associated with these infections. These studies may eventually lead to the development of novel broad spectrum antibacterial agents for these pathogens. PUBLIC HEALTH RELEVANCE: We envision that YopH inhibitors may be valuable for treating naturally occurring Yersinia pestis infection, e.g. as a supportive complement to antibiotics. Perhaps more importantly, we anticipate that the compounds may eventually be useful to combat infectivity of several other pathogens that share a similar toxin-phosphatase mediated activity, including Salmonella enterica, Francisella tularensis, Chlamydia psiticai, and Strep. Pneumonia, possibly leading to novel broad spectrum antibacterial agents.