Nitric oxide-releasing prodrug for the treatment of complex Mycobacterium abscessus 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 in vivo. Its efficacy in inhibiting growth or killing mycobacteria was explored in vitro 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 Mycobacterium abscessus isolates demonstrated no resistance to MD3. When administered directly into the lung via intra-tracheal administration in mice, MD3 demonstrated significant reduction in M. abscessus bacterial load in both acute and chronic models of M. abscessus lung infection. In summary, MD3 is a promising treatment for complex NTM pulmonary infection, specifically those caused by M. abscessus, and warrants further exploration as a therapeutic.

Biofilm Dispersal, Reduced Viscoelasticity, and Antibiotic Sensitization via Nitric Oxide-Releasing Biopolymers.

Compared to planktonic bacteria, biofilms are notoriously difficult to eradicate due to their inherent protection against the immune response and antimicrobial agents. Inducing biofilm dispersal to improve susceptibility to antibiotics is an attractive therapeutic avenue for eradicating biofilms. Nitric oxide (NO), an endogenous antibacterial agent, has previously been shown to induce biofilm dispersal, but with limited understanding of the effects of NO-release properties. Herein, the antibiofilm effects of five promising NO-releasing biopolymer candidates were studied by assessing dispersal, changes in biofilm viscoelasticity, and increased sensitization to tobramycin after treatment with NO. A threshold level of NO was needed to achieve biofilm dispersal, with longer-releasing systems requiring lower concentrations. The most positively charged NO-release systems (from the presence of primary amines) led to the greatest reduction in viscoelasticity of Pseudomonas aeruginosa biofilms. Co-treatment of tobramycin with the NO-releasing biopolymer greatly decreased the dose of tobramycin required to eradicate tobramycin-susceptible and -resistant biofilms in both cellular and tissue models.

Visible and near-infrared emitting heterotrimetallic lanthanide-aluminum-sodium 12-metallacrown-4 compounds: discrete monomers and dimers.

The luminescence properties of two types of heterotrimetallic aluminum-lanthanide-sodium 12-metallacrown-4 compounds are presented here, LnNa(ben)4[12-MCAl(III)N(shi)-4] (LnAl4Na) and {LnNa[12-MCAl(III)N(shi)-4]}2(iph)4 (Ln2Al8Na2), where Ln = GdIII, TbIII, ErIII, and YbIII, MC is metallacrown, ben- is benzoate, shi3- is salicylhydroximate, and iph2- is isophthalate. The aluminum-lanthanide-sodium metallacrowns formed with benzoate are discrete monomers while, upon replacement of the benzoate with the dicarboxylate isophthalate, two individual metallacrowns can be joined to form a dimer. In the solid state, the terbium version of each structure type displays emission in the visible region, and the erbium and ytterbium complexes emit in the near-infrared. The luminescence lifetimes (τobs) and quantum yields have been collected under ligand excitation (QLLn) for both LnAl4Na monomers and Ln2Al8Na2 dimers. Several of these values tend to be shorter (luminescence lifetimes) and smaller (quantum yields) than the corresponding values recorded for the structurally similar gallium-lanthanide monomer and dimer 12-MC-4 molecules. However, the quantum yield value recorded for the visible emitting Tb2Al8Na2 dimer, 43.9%, is the highest value observed in the solid state to date for a TbIII based metallacrown.