Tuberculosis (TB) remains a leading cause of mortality, currently responsible for 1.4 million deaths annually. The TB global health crisis is aggravated by the rise of multi- and extensively drug-resistant Mycobacterium (M.) tuberculosis. The World Health Organisation has declared multidrug-resistant TB both a security threat and a public health concern, and urges the development of shorter, safer, more effective TB therapies. Treatment of TB currently requires an extensive course of multiple antibiotics with diverse mechanisms of action. Thus, pre-clinical evaluation of new TB drug leads 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 against drug-sensitive and drug-resistant M. tuberculosis, in the absence of mammalian cytotoxicity. Here, we assessed synergistic and antagonistic effects of wollamides, in combination with approved anti-TB antibiotics, in inhibiting the growth and survival of M. tuberculosis. Our data indicate that wollamides do not antagonise current first-line TB antibiotics, alone or in currently used TB treatment regimens. Additionally, wollamides demonstrated synergy with a select subset of current TB antibiotics. These data add to the profile of desirable characteristics of wollamides and encourage further exploration of the utility of the wollamide pharmacophore as a lead for new TB antibiotics.