MDN-6, a Possible Therapeutic Candidate for Multidrug-Resistant and Extensively Drug-Resistant Mycobacterium tuberculosis

Background: The rise of antibiotic-resistant Mycobacterium tuberculosis strains has accelerated the hunt for novel drugs for tuberculosis (TB). Objectives: This study identified a novel compound with strong anti-TB efficacy against several resistant M. tuberculosis strains from a chemical library of naphthoquinone derivatives. Methods: The identified chemical was designated as MDN-6 (methyl-1,4-bis(2-(diethylamino)ethoxy)-2-naphthoate). Results: It significantly inhibited all the tested Mycobacterium strains, including 24 clinically isolated resistant strains. The minimum inhibitory concentrations of MDN-6 were between 0.02 and 25 g/mL. It also had partially synergistic activity against extensively drug-resistant M. tuberculosis when coupled with rifampicin and streptomycin. Additionally, MDN-6 demonstrated a superior post-antibiotic effect over isoniazid and exhibited comparable inhibitory efficacy against Mycobacterium marinum and Mycobacterium kansasii. Besides the antimicrobial effect, MDN-6 had a 50% lethal dosage (LD50) of 279.1 mg/kg in female BALB/c mice. Conclusions: MDN-6 is a promising anti-TB therapeutic candidate against drug-resistant M. tuberculosis. However, further investigation is necessary to elucidate the action mechanism and assess the drug’s in vivo therapeutic potential.