Next-generation 5-nitro heterocyclic antimicrobials against mucosal protists

University Of California, San Diego, La Jolla CA

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Abstract

? DESCRIPTION (provided by applicant): The 5-nitro drug, metronidazole (Mz), has been a mainstay of antimicrobial therapy for decades. Several of its simple derivatives such as tinidazole combine similar activity profiles with improved pharmacokinetic properties, but resistance to existing nitro drugs is increasing. Although commercial development of this drug class largely ceased decades ago, work by us and others over the last several years has shown that extensive modifications of the basic 5-nitroheterocyclic ring can lead to marked enhancement in activity against different microbes compared to existing drugs. These data suggest that Mz and other approved nitro drugs do not possess optimal activity in this drug class, yet important questions about the potential utility of novel nitro compounds must be addressed to advance their development as next-generation nitro drugs for clinical use: Is it possible to develop improved nitro drugs with broad-spectrum activity, or do enhanced activities exist only in microbe-specific fashion? Do new nitro drugs have different targets that can be exploited for overcoming resistance to existing drugs? What are the optimal pharmacokinetic properties of novel nitro drugs for maximal efficacy and potency against infections with different target microbes? Can new nitro drugs be developed with improved dosing regimens compared to existing drugs? Answers to these questions are not only critical for assessing the therapeutic potential of new nitro drugs, but are also key for identifying new leads for specific indications. The project will address these questions with a focus on two important protozoan pathogens, Trichomonas vaginalis and Giardia lamblia. We will evaluate a newly synthesized library of ~1,200 nitro drugs for activity against a broad range of drug-sensitive and drug-resistant strains of the target protozoa to identify library compounds more potent than Mz. Electrochemical approaches will be employed for determining the redox properties of the most potent nitro compounds to gain new fundamental clues about their mechanisms of action and potential toxicity. Subsequently, we will introduce new structural modifications into the top leads and evaluate them for bioactivity, cytotoxicity, electrochemical characteristics, and propensity to develop new drug resistance. Finally, we will evaluate the most promising nitro compounds for efficacy, potency, and pharmacokinetics in different murine models of protozoal infections. Upon completion of the proposed research, we expect to have elucidated broadly applicable principles that govern optimal efficacy of next-generation nitro-heterocyclic agents in the treatment of the clinically important parasitic diseases trichomoniasis and giardiasis. The comprehensive data sets to be generated will also be instrumental in selecting the most promising candidates as novel leads for the improved treatment of these infections, and potentially infections with other important pathogens, including Entamoeba histolytica, Trypanosoma cruzi, Helicobacter pylori, and Clostridium difficile, which can be treated with nitro antimicrobials.