The percent survival of G. mellonella wax worms infected with A. baumannii (AB 17978) and concomitantly treated with 67 μg/larva SCH-79797, 67 μg/larva gentamicin, 67 μg/larva rifampicin, or 67 μg/larva meropenem. p values are determined from a Mantel-Cox test using Prism (n.s., p ≥0.05 ∗p < 0.05). Data in (E) represents a typical cohort (n = 12) from a biological triplicate and the pooled results are presented in (F). The percent survival of non-infected G. mellonella wax worms after treatment with 2 μL/larva of 100% DMSO, 67 μg/larva SCH-79797, 67 μg/larva gentamicin, 67 μg/larva rifampicin, or 67 μg/larva meropenem.
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Trimethoprim and nisin resistant mutants were obtained from serial passaging in respective antibiotics. Fold increase in the susceptibility of S. aureus MRSA USA300 mutants to the indicated antibiotics. Fold increase in resistance of A. baumannii AB17978 to SCH-79797 and gentamicin after 5 days of serial passaging in each drug. Fold increase in resistance of S. aureus MRSA USA300 to SCH-79797, novobiocin, trimethoprim, or nisin after 25 days of serial passaging in each drug. Each data point represents 3 independent samples and 3 technical replicates.
Colony forming units (CFU mL -1) after 3-hour treatment of S. aureus MRSA USA300 with solvent only (1% DMSO), and 6.3 μg/mL SCH-79797 (1X MIC), or 4.0 μg/mL novobiocin (5X MIC). This promising antibiotic lead suggests that combining multiple MoAs onto a single chemical scaffold may be an underappreciated approach to targeting challenging bacterial pathogens. Building on the molecular core of SCH-79797, we developed a derivative, Irresistin-16, with increased potency and showed its efficacy against Neisseria gonorrhoeae in a mouse vaginal infection model. This pipeline demonstrates that SCH-79797 has two independent cellular targets, folate metabolism and bacterial membrane integrity, and outperforms combination treatments in killing methicillin-resistant Staphylococcus aureus (MRSA) persisters. To characterize its MoA, we combined quantitative imaging, proteomic, genetic, metabolomic, and cell-based assays. Here, we characterize a compound, SCH-79797, that kills both Gram-negative and Gram-positive bacteria through a unique dual-targeting mechanism of action (MoA) with undetectably low resistance frequencies. Of particular concern, no new antibiotic classes have been approved for treating Gram-negative pathogens in decades.
The rise of antibiotic resistance and declining discovery of new antibiotics has created a global health crisis.
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