Isoindolinones as Antimicrobial Agents

Antibiotic resistance among common pathogens is a serious public health problem because it compromises our ability to treat many infectious diseases. The problem has been compounded by the lack of discovery of new antibiotics that act in novel ways. Such compounds are critically needed as bacterial resistance to older antibiotics, and even their newer derivatives, is growing. <P> The goal of our work is to develop a new set of antibacterial compounds that we have discovered, the isoindolinone derivative, as agents that are active against Gram-positive pathogens. <P> In this Phase I SBIR feasibility study we ask a simple question: Can we demonstrate that our novel isoindolinone compounds have a good potential to lead to a new antibacterial drug? We will determine the general mechanism of action of our current lead compound. We will also prepare additional analogs to identify the general structural activity relationship of our isoindolinone derivatives. Our studies will show if we are able to prepare selective and druggable compounds suitable for further development in a Phase II study. Specifically, we plan to determine the mechanism of action of the isoindolinone class by determining if our lead compound perturbs the synthesis rates of protein, RNA, and DNA. We will also assess the ability of our lead compound to induce resistance and determine the synergy and antagonism of our lead compound with antibiotics of known mechanism of action. We will also prepare a highly focused set of analogs of our lead compound, in order to determine an optimal substitution pattern around a key aromatic ring. <P>PUBLIC HEALTH RELEVANCE: The ability to treat bacterial infections has become compromised by a growing resistance among common bacteria to antibiotics; this has become a significant public health problem. We have identified a novel structural class of antibacterial agents, and will study the mechanism of action and prepare a select set of analogs to evaluate for antibacterial activity. If successful, this project will provide a new class of antibacterial agents to combat the problem of antibiotic resistance.