Clostridium difficile is a Gram positive, spore forming anaerobic bacteria that is the leading cause of healthcare-associated diarrhoea.1 It imparts a significant burden on the community, estimated to cost the USA more than $496 million annually.2 One of main treatments for C. difficile infection is oral vancomycin, a glycopeptide antibiotic. However, vancomycin treatment fails in ~ 20% of patients resulting in high relapse rates.3,4 In addition, increasing resistance to vancomycin has been observed and new treatments are highly desired.5,6 We have developed vancomycin analogues that contain additional elements designed to improve binding to bacterial membranes, the site of vancomycin’s target. These compounds are 500 fold more active than vancomycin against methicillin resistant Staphylococcus aureus (MRSA), vancomycin resistant S. aureus and vancomycin resistant enterococci. Vancomycin analogues are presented here that are 30 fold more potent than vancomycin and 15 times more potent than metronidazole against C. difficile in in vitro assays and with improved bactericidal activity compared to vancomycin. A comparison of MIC activity against C. difficile with the superbugs mentioned above is highlighted.