A Dual-Mechanism Antibiotic Kills Gram-Negative Bacteria and Avoids Drug Resistance

Abstract

The rise of antibiotic resistance and declining discovery of new antibiotics have created a global health crisis. Of particular concern, no new antibiotic classes have been approved for treating Gram-negative pathogens in decades. 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. In an animal host model, SCH-79797 reduces pathogenesis of Acinetobacter baumannii, a drug-resistant Gramnegative pathogen. To characterize the MoA of SCH-79797 we combined quantitative imaging, proteomic, genetic, metabolomic, and cell-based assays. This pipeline shows that SCH-79797 has two independent cellular targets, folate metabolism and bacterial membrane integrity, and outperforms combination treatments with other antifolates and membrane disruptors in killing MRSA persisters. Thus, SCH-79797 represents a promising lead antibiotic and suggests that combining multiple MoAs onto a single chemical scaffold may be an underappreciated approach to target challenging bacterial pathogens..

Nontoxic Cobalt(III) Schiff Base Complexes with Broad‐Spectrum Antifungal Activity

“…We therefore opted to conduct first experimentsi nt he greater wax moth Galleria mellonella,a ni nsect whose larvae have been used for antimicrobial toxicitys tudies previously. [29] Toxicity data from this low cost animal model has been shown to correlate well with data from rodentm odels. [29b] Compounds 1-3 were dissolved in DMSO and diluted to final concentrations of 1 mM, 100 mMa nd 10 mM.…”

Understanding of Pharmacy Students towards Antibiotic Use, Antibiotic Resistance and Antibiotic Stewardship Programs: A Cross-Sectional Study from Punjab, Pakistan

“…Antibiotics are used to treat multiple infections due to their inherited ability to restrict the growth of or killing pathogenic microorganisms [ 1 ]. However, the continuous irrational, and injudicious use of antibiotics has led to antibiotic resistance (ABR).…”

Mining for novel antibiotics in the age of antimicrobial resistance

“…High‐throughput screenings have been also successfully used for the discovery of antimicrobials with novel mechanisms of action (Kitamura et al ., 2018). In this respect, the screening of a library of 33 000 small molecules resulted in the identification of SCH‐79797 as a potent antibacterial agent against important Gram‐negative and Gram‐positive pathogens including Acinetobacter baumannii , Staphylococcus aureus , Neisseria gonorrhoeae or Enterococcus faecalis with undetectable AMR development (Martin et al ., 2020). Significantly, SCH‐79797 effectiveness was demonstrated against several AMR isolates, while the inability to isolate SCH‐79797‐resistant mutants hindered the elucidation of the mechanism of action (MoA) of this antibacterial.…”

“…Significantly, SCH‐79797 effectiveness was demonstrated against several AMR isolates, while the inability to isolate SCH‐79797‐resistant mutants hindered the elucidation of the mechanism of action (MoA) of this antibacterial. To overcome this difficulty, in a recently published Cell article the authors combined quantitative imaging, thermal proteome profiling, CRISPR interference sensitivity, metabolomics, enzymology and quantitative flow cytometry to reveal that SCH‐79797 targets both membrane integrity and folate metabolism (Martin et al ., 2020). Subsequent assays demonstrated that this molecule, due to its double antibacterial activities, outperforms the effects of certain different antibiotic combinations in the treatment of AMR bacteria.…”

“…One of these derivatives, Irresistin‐16 (IRS‐16), exhibited enhanced antibacterial activity in comparison with SCH‐79797, and it was efficient for treating N. gonorrhoeae in a mouse vaginal infection model with low host toxicity. The authors highlighted that combining several MoA in a single chemical scaffold may be an efficient approach to treat infections caused by AMR pathogens (Martin et al ., 2020).…”