Fusidic acid-based drug combinations exhibit enhanced activity against Mycobacterium tuberculosis

Tuberculosis (TB) imposes a major burden on global public health which is exacerbated by the escalating number of multidrug-resistant (MDR)-TB cases. There is consequently an urgent need for new anti-TB drugs and combination regimens. We have investigated the natural product antibiotic fusidic acid (FA) for repurposing against Mycobacterium tuberculosis, the causative agent of TB. Here, we report the results of synergy screens combining FA with a panel of approved anti-TB agents. Checkerboard and time-kill kinetics assays identified seven compounds from different chemical classes that synergized with FA in inhibiting the growth of M. tuberculosis in vitro: rifampicin (RIF), a rifamycin and frontline anti-TB drug; the macrolides, erythromycin (ERY), clarithromycin (CLR), and roxythromycin (ROX); the oxazolidinone, linezolid (LZD); the aminoglycoside, streptomycin (STR); and the aminocyclitol, spectinomycin (SPC). Among these, the strongest synergies were observed where FA was combined with SPC and ERY. Moreover, the FA-RIF combination was cidal, while all other FA combinations were bacteriostatic. These results provide in vitro evidence of the potential utility of FA-containing combinations against M. tuberculosis.