Medicinal Chemistry

细菌的交流，耐药性和毒力机制仍然是小

Bacterial communication, resistance, and virulence mechanisms remain underrepresented targets for small molecule-based medicinal chemistry. The relatively narrow focus of antimicrobial drug discovery is particularly acute in the area of Gram-negative infections, a class that includes pathogens relevant to potential acts of bioterrorism (Yersinia pestis, Burkholderia pseudomalleii), emerging infections (Escherichia co// O157:H7), and persistent infections (Pseudomonas aeruginsoa). There are compelling reasons to understand virulence mechanisms, and to use small molecule chemistry to do so. Drugs directed at virulence targets are less likely to provoke a resistance response in the bacteria. Novel drugs, and drugs directed at novel targets, are also less likely to be deflected by pre-existing drug resistance mechanisms in the bacteria. In light of this, we are developing novel compounds directed at novel virulence targets as potential therapeutics and as microbiology research tools. In this proposal we outline our progress and plans using chemical biology/medicinal chemistry to understand and ultimately manipulate two virulence-related systems, type III secretion (T3SS) and bis-(3'-5') cyclic diguanilic acid (c-di-GMP) signaling. For both projects, the goals are to synthesize molecules that will (a) enable understanding the molecular details of the dynamics and architechture of these complex oligomeric systems,(b) to validate targets within these systems for drug discovery, and (c) to produce lead candidates for development as human therapeutics targeting these systems. In the T3SS project we have synthesized derivatives of our original high-throughput screen hit (TTSS29) that not only improve upon its activity 10 and 100-fold but also improve the potential of this chemotype to be a realistic therapeutic. When considered along with the earlier purchased compounds, our panel of novel synthetic compounds¿now over 50- provide the guidance we need for further refinements in the 2-iminothiazolidinone class to which TTSS29 belongs. In the c-di-GMP project, we have synthesized a novel class stable analogs of the known signaling molecule (i.e. c-di-GMP itself) and several seco-di-GMP analogs of the acyclic dimer, pGpG, a molecule that may have as-yet-unreported signaling properties of its own. Currently, no small molecule inhibitors, agonists, or antagonists of the c-di-GMP pathway have been reported. We will evaluate our novel c-di-GMP and s-di-GMP analogs as inhibitors of the upregulating cyclase, the downregulating phosphodiesterase, and as agonists /antagonists of known cdi- GMP mediated responses. From these data, and from an in silico screen we describe herein, we will create new compounds intended to validate, and ultimately exploit, c-di-GMP signalling as a therapeutic target in Gram-negative infections .