Tuberculosis (TB) is the world’s leading cause of mortality by a single infectious agent, currently responsible for 1.5 million deaths annually. The TB global health crisis is exacerbated by the rise of multi- and extensively-drug resistant Mycobacterium tuberculosis. The World Health Organization urges that the development of shorter, safer, and more effective therapies for the treatment of drug-sensitive and drug-resistant TB is central to alleviating the burden of TB on global health and economies. Current TB treatment requires an extensive course of multiple antibiotics with diverse mechanisms of action. Thus, pre-clinical evaluation of new TB drug lead compounds requires assessment of potential interactions with existing TB antibiotics. We recently reported a new class of Streptomyces-derived cyclic hexapeptides, Wollamides, which exert anti-mycobacterial activity with no detectable mammalian cytotoxicity. Building on our extensive structure-activity-relationship-based initial characterisations of Wollamide activity, we assessed potential synergistic and antagonistic effects of Wollamides in combination with approved anti-TB antibiotics. Our data indicate that Wollamides synergise with a select subset of current TB antibiotics, and do not antagonise current first-line TB treatment agents. These findings encourage further exploration of the utility of the Wollamide pharmacophore as an antibiotic against Mycobacterium tuberculosis.