Since the 1960s, there has been a decline in the discovery of new antibiotics, particularly against Gram-negative bacteria. Increases in antibiotic resistance call for an urgent need to identify suitable candidates for broad-spectrum antibiotics with novel mechanisms of action (MoA).
In a recent study, Martin, Sheehan, Bratton et al. used a small-molecule screen to identify a compound (SCH-79797) that shows promising bactericidal activity against both Gram-positive and Gram-negative bacteria. After confirming antibiotic activity against a variety of pathogens in vitro, the authors showed that SCH-79797 is effective against a lethal dose of Acinetobacter baumannii in the wax worm Galleria mellonella, prolonging survival without any noticeable toxicity. The authors found that SCH-79797 has a low frequency of resistance in methicillin-resistant Staphylococcus aureus and A. baumannii in vitro. Remarkably, no resistant clones emerged, despite using sub-lethal concentrations over 5–30 passages, indicating sustained action that is not species specific.
To investigate the MoA, the authors turned to image-based bacterial cytological profiling and compared cell death phenotypes between SCH-79797 and established antibiotics with known MoAs. Their analysis showed that the MoA of SCH-79797 was distinct from any other tested antibiotic. Using high-throughput thermal proteome profiling followed by a screen with a Bacillus subtilis CRISPRi knockdown library, the authors identified a dihydrofolate reductase (DHFR; an Escherichia coli FolA homologue) as the target of SCH-79797. In vitro enzyme assays showed that SCH-79797 directly inhibits DHFR activity. SCH-79797 was also found to be distinct from other FolA inhibitors like trimethoprim, in that it also affects bacterial cell membrane integrity, conferring a dual MoA. The authors also observed that a single treatment with SCH-79797 was more potent than a combination of two antibiotics — trimethoprim and nisin, or polymyxin B and daptomycin.
Delving into the chemistry behind the dual MoA, the authors found that the pyrroloquinazolinediamine core of SCH-79797 contributes to DHFR inhibition while the hydrophobic isopropylbenzene targets membrane integrity. To further demonstrate this, they synthesized a derivative, Irresistin-16 (IRS-16), that is more hydrophobic than SCH-79797. IRS-16 recapitulated the dual MoA on bacteria both in culture and in vivo, reducing the vaginal burden of Neisseria gonorrhoeae in a mouse infection model for gonorrhoea.
In sum, this study presents a promising candidate for a novel broad-spectrum antibiotic and highlights the potential in combining multiple MoAs into a single chemical for the treatment of diverse bacterial pathogens.
Nature Reviews Drug Discovery 19, 512 (2020)
This article originally appeared in Nat. Rev. Microbiol. (https://doi.org/10.1038/s41579-020-0401-4)