Fragment-based development of small molecule inhibitors targeting cholesterol metabolism.

( ) is the world's most deadly infectious pathogen and new drugs are urgently required to combat the emergence of multi-(MDR) and extensively-(XDR) drug resistant strains. The bacterium specifically upregulates sterol uptake pathways in infected macrophages and the metabolism of host-derived cholesterol is essential for long-term survival Here, we report the development of antitubercular small molecules that inhibit the cholesterol oxidases CYP125 and CYP142, which catalyze the initial step of cholesterol metabolism. An efficient biophysical fragment screen was used to characterize the structure-activity relationships of CYP125 and CYP142, and identify a non-azole small molecule that can bind to the heme cofactor of both enzymes.

Expression and purification of Mycobacterium tuberculosis F-dependent glucose-6-phosphate dehydrogenase enzyme using Escherichia coli.

Since their discovery in Mycobacterium tuberculosis (Mtb), F-dependent enzymes have been identified as both important drug targets and potential industrial biocatalysts, including for bioremediation of otherwise recalcitrant substrates. Mtb-FGD1, utilizes glucose 6-phosphate (G6P) as an electron donor for the reduction of F. Current expression systems for Mtb-FGD1 use Mycobacterium smegmatis as host, because of the tendency for it to form inclusion bodies in E.

Will they come back? Evaluation of health student placements in remote and very remote regions of Australia.

Background: Despite the benefits of rural placements in attracting healthcare professionals to rural areas, there remains a gap in understanding the specific impact of placements in remote and very remote areas of Australia, particularly within the unique context of the Kimberley region. There is a need to elucidate differences across geographical areas and contribute to the knowledge about the specifics of where and how student placement programs work. This research explored the impact of a remote placement program at Majarlin Kimberley Centre for Remote Health ('Majarlin') on educational outcomes and workforce intentions of participating students.

Targeting the PREX2/RAC1/PI3Kβ Signaling Axis Confers Sensitivity to Clinically Relevant Therapeutic Approaches in Melanoma.

Metastatic melanoma remains a major clinical challenge. Large-scale genomic sequencing of melanoma has identified bona fide activating mutations in RAC1, which are associated with resistance to BRAF-targeting therapies. Targeting the RAC1-GTPase pathway, including the upstream activator PREX2 and the downstream effector PI3Kβ, could be a potential strategy for overcoming therapeutic resistance, limiting melanoma recurrence, and suppressing metastatic progression.

A stepped wedge randomised controlled trial assessing the efficacy and patient acceptability of virtual clinical pharmacy in rural and remote Australian hospitals.

Background: Despite medication being the most common healthcare intervention and medication-related incidents being common in hospitals, many rural and remote hospitals in Australia lack onsite pharmacy services due to resource constraints. A Virtual Clinical Pharmacy Service (VCPS) staffed by two senior, rural generalist hospital pharmacists assigned to four hospitals each was implemented in rural and remote facilities to determine whether the VCPS increased adherence to National Safety and Quality Health Service Standards (NSQHS).

Methods: A stepped-wedge randomised controlled trial was employed to sequentially implement a telehealth pharmacy service at one-month intervals in eight hospitals.