Isoquinoline Antimicrobial Agent: Activity against Intracellular Bacteria and Effect on Global Bacterial Proteome

A new class of alkynyl isoquinoline antibacterial compounds, synthesized via Sonogashira coupling, with strong bactericidal activity against a plethora of Gram-positive bacteria including methicillin- and vancomycin-resistant Staphylococcus aureus (S. aureus) strains is presented. HSN584 and HSN739, representative compounds in this class, reduce methicillin-resistant S. aureus (MRSA) load in macrophages, whilst vancomycin, a drug of choice for MRSA infections, was unable to clear intracellular MRSA. Additionally, both HSN584 and HSN739 exhibited a low propensity to develop resistance. We utilized comparative global proteomics and macromolecule biosynthesis assays to gain insight into the alkynyl isoquinoline mechanism of action. Our preliminary data show that HSN584 perturb S. aureus cell wall and nucleic acid biosynthesis. The alkynyl isoquinoline moiety is a new scaffold for the development of potent antibacterial agents against fatal multidrug-resistant Gram-positive bacteria.

Automated summary

This study presents a new class of alkynyl isoquinoline antibacterial compounds, synthesized via Sonogashira coupling, which exhibit strong bactericidal activity against a range of Gram-positive bacteria including methicillin- and vancomycin-resistant Staphylococcus aureus strains. Representative compounds in this class, HSN584 and HSN739, are capable of reducing methicillin-resistant S. aureus load in macrophages and show a low propensity for developing resistance. Comparative global proteomics and macromolecule biosynthesis assays suggest that HSN584 perturbs S. aureus cell wall and nucleic acid biosynthesis. The alkynyl isoquinoline moiety holds promise as a new scaffold for the development of potent antibacterial agents against multidrug-resistant Gram-positive bacteria.