While thiopeptides exhibit strong bactericidal activity and selectivity, their low solubility remains a barrier to clinical use. Research into synthetic routes for thiopeptide modifications is ongoing , and poses great potential for translating these compounds into the clinic. Notably, recent findings show that some thiopeptides can permeate the outer membrane of certain Gram-negative species via species-specific porin proteins , highlighting their potential for developing broad-spectrum antibiotics. Further work is needed to provide a detailed SAR of thiopeptides and to explore bioisosteric replacements that can improve their solubility and expand the therapeutic scope of thiopeptides.