Overcoming Intrinsic and Acquired Resistance Mechanisms Associated with the Cell Wall of Gram-Negative Bacteria
Authors: Impey, Rachael E.; Hawkins, Daniel A.; Sutton, J. Mark; Soares da Costa, Tatiana P.
The global increase in multi-drug-resistant bacteria is severely impacting our ability to effectively treat common infections. For Gram-negative bacteria, their intrinsic and acquired resistance mechanisms are heightened by their unique cell wall structure. The cell wall, while being a target of some antibiotics, represents a barrier due to the inability of most antibacterial compounds to traverse and reach their intended target. This means that its composition and resulting mechanisms of resistance must be considered when developing new therapies. Here, we discuss potential antibiotic targets within the most well-characterised resistance mechanisms associated with the cell wall in Gram-negative bacteria, including the outer membrane structure, porins and efflux pumps. We also provide a timely update on the current progress of inhibitor development in these areas. Such compounds could represent new avenues for drug discovery as well as adjuvant therapy to help us overcome antibiotic resistance.
Microparticles in the pathogenesis of TB: Novel perspectives for diagnostic and therapy management of Mycobacterium tuberculosis infection
Authors: Moreira, Josimar Dornelas; Silva, Henrique Rodrigues; Coelho Peixoto de Toledo, Vicente de Paulo; Pinto Dabes Guimaraes, Tania Mara
Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis, usually chronic and has a progressive clinical course. Despite the availability of effective chemotherapy, TB is a leading killer of young adults worldwide and the global multi-drug resistant TB is reaching epidemic proportions. Interrupt transmission through early detection and treatment of the patients is a main element of the drug-resistant TB control strategy. However, many drugable targets in pathogens are already inhibited by current antibiotics and there is not a biomarker that indicate normal or pathogenic biological processes, or pharmacological responses to therapeutic intervention. Studies directed at evaluate key elements of host response to infection may identify biomarkers with measurable characteristics that indicate pathogenic biological processes. Cell-derived microparticles (MPs) are membrane-coated vesicles that represent subcellular elements and have been identified increasingly in a broad range of diseases and emerging as potential novel biomarker to pathological processes. In addition, MPs carry contents from their cells of origin as bioactive molecules as cytokines, enzymes, surface receptors, antigens and genetic information and may provide a means of communication between cells. Molecules-loaded MPs may interplay with the immune system and therefore can acts on inflammation, cell activation and migration. Therefore, MPs may be an important factor to immune process during Mtb infection, especially in pulmonary granulomas and influence the outcome of infection. Their characterization may facilitate an appropriate diagnosis, optimize pharmacological strategies and might be further explored as potential targets for future clinical interventions.