G-quadruplexes as antimicrobial targets

Escalating antibiotic resistance and poor options for many parasitic infections, including neglected tropical diseases, demand new antimicrobial strategies. G-quadruplexes (G4s), which are noncanonical nucleic acid structures, are emerging targets in microbial genomes. We summarize evidence for G4 formation in bacteria and parasites, which is provided by phenotypic and chemical-biology datasets, whereas evidence in support of fungal G4 targeting remains nascent, with fewer studies and limited mechanistic validation. After integrating genomics and bioinformatics data, we argue that microbial G4s are a promising yet incompletely validated target class, backed by expanding catalogues of putative G4-forming loci and ligand-associated phenotypes. For many reported ligands, however, direct intracellular G4 engagement and causal links to the killing or growth inhibition of microbes are still unproven. We discuss ligand chemotypes, design principles, and pharmacological considerations in the translation of G4s into therapeutics.