Nitric Oxide-releasing Prodrug for the Treatment of Complex Infections

Non-tuberculosis mycobacteria (NTM) can cause severe respiratory infection in patients with underlying pulmonary conditions, and these infections are extremely difficult to treat. In this report, we evaluate a nitric oxide (NO)-releasing prodrug [methyl tris diazeniumdiolate (MD3)] against a panel of NTM clinical isolates and as a treatment for acute and chronic NTM infections . Its efficacy in inhibiting growth or killing mycobacteria was explored alongside evaluation of the impact to primary human airway epithelial tissue. Airway epithelial tissues remained viable after exposure at concentrations of MD3 needed to kill mycobacteria, with no inherent toxic effect from drug scaffold after NO liberation. Resistance studies conducted via serial passage with representative isolates demonstrated no resistance to MD3. When administered directly into the lung via intra-tracheal administration in mice, MD3 demonstrated significant reduction in bacterial load in both acute and chronic models of lung infection. In summary, MD3 is a promising treatment for complex NTM pulmonary infection, specifically those caused by , and warrants further exploration as a therapeutic.