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Bacterial persistence coupled with biofilm formation is directly associated with failure of antibiotic treatment of tuberculosis. We have now identified 4-(4,7-DiMethyl-1,2,3,4-tetrahydroNaphthalene-1-yl)Pentanoic acid (DMNP), a synthetic diterpene analogue, as a lead compound that was capable of suppressing persistence and eradicating biofilms in Mycobacterium smegmatis. By using two reciprocal experimental approaches – Δ rel Msm and Δ relZ gene knockout mutations versus rel Msm and relZ overexpression technique – we showed that both Rel Msm and RelZ (p)ppGpp synthetases are plausible candidates for serving as targets for DMNP. In vitro , DMNP inhibited (p)ppGpp-synthesizing activity of purified Rel Msm in a concentration-dependent manner. These findings, supplemented by molecular docking simulation, suggest that DMNP targets the structural sites shared by Rel Msm , RelZ, and presumably by a few others as yet unidentified (p)ppGpp producers, thereby inhibiting persister cell formation and eradicating biofilms. Therefore, DMNP may serve as a promising lead for development of antimycobacterial drugs. [Display omitted] • DMNP is a synthetic diterpene analogue inhibiting mycobacterial persistence • (p)ppGpp is an essential cell regulator of persistence and biofilm formation • DMNP targets Rel Msm , RelZ (p)ppGpp synthetases and inhibits their activities • Lack of (p)ppGpp reduces cell survival by limiting persistence and biofilm formation Tkachenko et al. revealed that DMNP, a synthetic analogue of natural marine diterpene erogorgiaene, binds to the structurally similar sites of Rel Msm , RelZ, and presumably of some other as yet unidentified (p)ppGpp producers thereby inhibiting persister cell formation and eradicating biofilms. [ABSTRACT FROM AUTHOR]