3-Oxo-acyl-acyl carrier protein (ACP)
reductase (FabG) plays a
key role in the bacterial fatty acid synthesis II system in pathogenic
microorganisms, which has been recognized as a potential drug target.
FabG catalyzes reduction of a 3-oxo-acyl-ACP intermediate during the
elongation cycle of fatty acid biosynthesis. Here, we report gene
deletion experiments that support the essentiality of this gene in P. aeruginosa and the identification of a number of small
molecule FabG inhibitors with IC50 values in the nanomolar
to low micromolar range and good physicochemical properties. Structural
characterization of 16 FabG-inhibitor complexes by X-ray crystallography
revealed that the compounds bind at a novel allosteric site located
at the FabG subunit–subunit interface. Inhibitor binding relies
primarily on hydrophobic interactions, but specific hydrogen bonds
are also observed. Importantly, the binding cavity is formed upon
complex formation and therefore would not be recognized by virtual
screening approaches. The structure analysis further reveals that
the inhibitors act by inducing conformational changes that propagate
to the active site, resulting in a displacement of the catalytic triad
and the inability to bind NADPH.
Leprosy is a chronic infectious disease and is a major source of morbidity in developing countries. Leprosy is caused by the obligate intracellular bacterium Mycobacterium leprae, which infects as primary target Schwann cells. Lepromatous leprosy exhibits multiple lesions of the skin, eyes, nerves, and lymph nodes. The sites of infection are characterized by the presence of foamy macrophages, fully packed with lipid droplets (LDs), which are induced by M. leprae. In the last years, it has become evident that M. tuberculosis imports lipids from foamy macrophages and is dependent on fatty acids for growth in infected macrophages. M. leprae seems to have similar mechanisms for scavenging lipids from the host. But due to the inability to culture M. leprae on laboratory media, research progresses only slowly. However, in the last years, substantial progress has been made in the field of lipid metabolism in M. leprae. Herein, we will present and summarize the lipid droplets formation and the metabolism of lipids during M. leprae infection.
Tuberculosis (TB) is the leading global cause of death from a single infectious agent. Registered incidence rates are low, especially in low-resource countries with weak health systems, due to the disadvantages of current diagnostic techniques. A major effort is directed to develop a point-of-care (POC) platform to reduce TB deaths with a prompt and reliable low-cost technique. In the frame of the European POCKET Project, a novel POC platform for the direct and non-invasive detection of TB in human urine was developed. The photonic sensor is integrated in a disposable cartridge and is based on a highly sensitive Mach-Zehnder Interferometer (MZI) transducer combined with an on-chip spectral filter. The required elements for the read-out are integrated in an instrument prototype, which allows real-time monitoring and data processing. In this work, the novel POC platform has been employed for the direct detection of lipoarabinomannan (LAM), a lipopolysaccharide found in the mycobacterium cell wall. After the optimization of several parameters, a limit of detection of 475 pg/mL (27.14 pM) was achieved using a direct immunoassay in undiluted human urine in less than 15 minutes. A final validation of the technique was performed using twenty clinical samples from TB patients and healthy donors, allowing the detection of TB in people regardless of HIV coinfection. The results show excellent correlation to those obtained with standard techniques. These promising results demonstrate the high sensitivity, specificity and applicability of our novel POC platform, which could be used during routine checkups in developing countries.
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