5-Nitroimidazole (5-NI) compounds are used to treat a variety of bacterial and parasitic infections. Metronidazole (Mz), a 5-NI drug, is a safe and affordable drug that has been used for nearly half a century to treat infections caused by intestinal pathogens. When combined with other medications Mz has successfully been used to treat H. pylori infections. H. pylori is a microaerophilic bacteria that causes a range of gastrointestinal diseases. While Mz is active against H. pylori, the treatment failure rate of Mz centered therapy is increasing (Peter J. Jenks 2002). Others have taken advantage of the ability to synthesize structurally diverse 5-NI compounds and have found that some of the newly derived compounds are highly potent compared to Mz (Jacqueline A. Upcroft 2006). We asked if 5-Ni compounds, apart from Mz, could reduce the growth rate of H. pylori and potentially function as new antibiotics. We show that 5-NI compounds are active against multiple strains of H. pylori. Also, we found four compounds that are able to overcome Mz-resistance. Finally, we propose a new method for gaining a better understating of Mz resistance mechanisms using a strain's compound activity profile coupled with phylogenetic tools

Metronidazole and other 5-nitroimidazoles (5-NI) are among the most effective antimicrobials available against many important anaerobic pathogens, but evolving resistance is threatening their long-term clinical utility. The common 5-NIs were developed decades ago, yet little 5-NI drug development has since taken place, leaving the true potential of this important drug class unexplored. Here we report on a unique approach to the modular synthesis of diversified 5-NIs for broad exploration of their antimicrobial potential. Many of the more than 650 synthesized compounds, carrying structurally diverse functional groups, have vastly improved activity against a range of microbes, including the pathogenic protozoa Giardia lamblia and Trichomonas vaginalis, and the bacterial pathogens Helicobacter pylori, Clostridium difficile, and Bacteroides fragilis. Furthermore, they can overcome different forms of drug resistance, and are active and nontoxic in animal infection models. These findings provide impetus to the development of structurally diverse, next-generation 5-NI drugs as agents in the antimicrobial armamentarium, thus ensuring their future viability as primary therapeutic agents against many clinically important infections.