Search

Tuberculosis, caused by Mycobacterium tuberculosis, claims ∼1.5 million lives annually. Effective chemotherapy is essential to control TB, however the emergence of drug-resistant strains of TB have seriously threatened global attempts to control and eradicate this deadly pathogen. Trehalose recycling viathe LpqY-SugABC importer is essential for the virulence and survival of Mtband inhibiting or hijacking this transport system is an attractive approach for the development of novel anti-tubercular and diagnostic agents. Therefore, we interrogated the drug-like compounds in the open-source Medicines for Malaria Pathogen Box and successfully identified seven compounds from the TB, kinetoplastids and reference compound disease sets that recognise LpqY. The molecules have diverse chemical scaffolds, are not specific trehalose analogues, and may be used as novel templates to facilitate the development of therapeutics that kill Mtbwith a novel mechanism of action viathe mycobacterial trehalose LpqY-SugABC transport system. more...

Securing novel, safe, and effective medicines to treat Mycobacterium tuberculosisremains an elusive goal, particularly influenced by the largely impervious Mtbenvelope that limits exposure and thus efficacy of inhibitors at their cellular and periplasmic targets. The impact of physicochemical properties on pharmacokinetic parameters that govern oral absorption and exposure at sites of infection is considered alongside how these properties influence penetration of the Mtbenvelope, with the likely influence of transporter proteins. The findings are discussed to benchmark current drugs and the emerging pipeline, whilst considering tactics for future rational and targeted design strategies, based around emerging data on Mtbtransporters and their structures and functions. more...

Mycobacterium tuberculosis(Mtb) is the causative agent of tuberculosis (TB) and has evolved an incredible ability to survive latently within the human host for decades. The Mtbpathogen encodes for a low number of ATP-binding cassette (ABC) importers for the acquisition of carbohydrates that may reflect the nutrient poor environment within the host macrophages. MtbUgpB (Rv2833c) is the substrate binding domain of the UgpABCE transporter that recognizes glycerophosphocholine (GPC), indicating that this transporter has a role in recycling glycerophospholipid metabolites. By using a combination of saturation transfer difference (STD) NMR and X-ray crystallography, we report the structural analysis of MtbUgpB complexed with GPC and have identified that MtbUgpB not only recognizes GPC but is also promiscuous for a broad range of glycerophosphodiesters. Complementary biochemical analyses and site-directed mutagenesis precisely define the molecular basis and specificity of glycerophosphodiester recognition. Our results provide critical insights into the structural and functional role of the MtbUgpB transporter and reveal that the specificity of this ABC-transporter is not limited to GPC, therefore optimizing the ability of Mtbto scavenge scarce nutrients and essential glycerophospholipid metabolites via a single transporter during intracellular infection. more...

Because of the emergence of antimicrobial resistance to traditional small-molecule drugs, cationic antimicrobial polymers are appealing targets. Mycobacterium tuberculosisis a particular problem, with multi- and total drug resistance spreading and more than a billion latent infections globally. This study reports nanoparticles bearing variable densities of poly(dimethylaminoethyl methacrylate) and the unexpected and distinct mechanisms of action this multivalent presentation imparts against Escherichia coliversus Mycobacterium smegmatis(model of M. tuberculosis), leading to killing or growth inhibition, respectively. A convergent “grafting to” synthetic strategy was used to assemble a 50-member nanoparticle library, and using a high-throughput screen identified that only the smallest (2 nm) particles were stable in both saline and complex cell media. Compared with the linear polymers, the nanoparticles displayed two- and eight-fold enhancements in antimicrobial activity against M. smegmatisand E. coli, respectively. Mechanistic studies demonstrated that the antimicrobial particles were bactericidal against E. colidue to rapid disruption of the cell membranes. Conversely, against M. smegmatisthe particles did not lyse the cell membrane but rather had a bacteriostatic effect. These results demonstrate that to develop new polymeric antituberculars the widely assumed, broad spectrum, membrane-disrupting mechanism of polycations must be re-evaluated. It is clear that synthetic nanomaterials can engage in more complex interactions with mycobacteria, which we hypothesize is due to the unique cell envelope at the surface of these bacteria. more...