rifampin and diphenyleneiodonium

In this study, a structure-activity relationship (SAR) compound series based on the NDH-2 inhibitor diphenyleneiodonium (DPI) was synthesised. Compounds were evaluated primarily for in vitro efficacy against Gram-positive and Gram-negative bacteria, commonly responsible for nosocomial and community acquired infections. In addition, we also assessed the activity of these compounds against Mycobacterium tuberculosis (Tuberculosis) and Plasmodium spp. (Malaria). This led to the discovery of highly potent compounds active against bacterial pathogens and malaria parasites in the low nanomolar range, several of which were significantly less toxic to mammalian cells.

Topics: Animals; Bacteria; Community-Acquired Infections; Cross Infection; Gram-Negative Bacteria; Gram-Positive Bacteria; Malaria; Mycobacterium tuberculosis; Onium Compounds; Structure-Activity Relationship

Indiscriminate use of antibiotics globally has lead to an increase in emergence of drug-resistant pathogens under both nosocomial, as well as more worryingly, in community setting as well. Further, a decrease in the corporate interest and financial commitment has exerted increasing pressure on a rapidly dwindling antimicrobial drug discovery and developmental program. In this context, we have screened the Library of Pharmacologically Active Compounds (LOPAC, Sigma) against Staphylococcus aureus and Mycobacterium tuberculosis to identify potent novel antimicrobial molecules amongst non-antibiotic molecules. Microplate-based whole cell growth assay was performed to analyze the antimicrobial potency of the compounds against Staphylococcus aureus and Mycobacterium tuberculosis. We identified diphenyleneiodonium chloride, a potent inhibitor of NADH/NADPH oxidase, as a broad-spectrum antibiotic potently active against drug resistant strains of Staphylococcus aureus and Mycobacterium tuberculosis. Intriguingly, the diphenyleneiodonium chloride was also very effective against slow-growing non-replicating Mtb persisters. FIC index demonstrated a strongly synergistic interaction between diphenyleneiodonium chloride and Rifampicin while it did not interact with INH. The antimicrobial property of the diphenyleneiodonium chloride was further validated in vivo murine neutropenic thigh S. aureus infection model. Taken together, these findings suggest that Diphenyleneiodonium chloride can be potentially repurposed for the treatment of tuberculosis and staphylococcal infections.

Topics: Animals; Anti-Bacterial Agents; Disease Models, Animal; Drug Repositioning; Drug Synergism; Enzyme Inhibitors; Mice; Microbial Viability; Mycobacterium tuberculosis; NADH, NADPH Oxidoreductases; Onium Compounds; Rifampin; Staphylococcal Infections; Staphylococcus aureus; Treatment Outcome; Tuberculosis