Restoring susceptibility to ß-lactam antibiotics in methicillin-resistant Staphylococcus aureus.

Infections by Staphylococcus aureus have been treated historically with ß-lactam antibiotics. However, these antibiotics have become obsolete in methicillin-resistant S. aureus by acquisition of the bla and mec operons. The presence of the ß-lactam antibiotic is detected by the sensor domains of BlaR and/or MecR, and the information is transmitted to the cytoplasm, resulting in derepression of the antibiotic-resistance genes. We hypothesized that inhibition of the sensor domain would shut down this response system, and ß-lactam susceptibility would be restored. An in silico search of 11 million compounds led to a benzimidazole-based hit and, ultimately, to the boronate 4. The X-ray structure of 4 is covalently engaged with the active-site serine of BlaR. Compound 4 potentiates by 16- to 4,096-fold the activities of oxacillin and of meropenem against methicillin-resistant S. aureus strains. The combination of 4 with oxacillin or meropenem shows efficacy in infected mice, validating the strategy.

Structural characterization of PaaX, the main repressor of the phenylacetate degradation pathway in Escherichia coli W: A novel fold of transcription regulator proteins.

PaaX is a transcriptional repressor of the phenylacetic acid (PAA) catabolic pathway, a central route for bacterial aerobic degradation of aromatic compounds. Induction of the route is achieved through the release of PaaX from its promoter sequences by the first compound of the pathway, phenylacetyl-coenzyme A (PA-CoA). We report the crystal structure of PaaX from Escherichia coli W. PaaX displays a novel type of fold for transcription regulators, showing a dimeric conformation where the monomers present a three-domain structure: an N-terminal winged helix-turn-helix domain, a dimerization domain similar to the Cas2 protein and a C-terminal domain without structural homologs. The domains are separated by a crevice amenable to harbour a PA-CoA molecule. The biophysical characterization of the protein in solution confirmed several hints predicted from the structure, i.e. its dimeric conformation, a modest importance of cysteines and a high dependence of solubility and thermostability on ionic strength. At a moderately acidic pH, the protein formed a stable folding intermediate with remaining α-helical structure, a disrupted tertiary structure and exposed hydrophobic patches. Our results provide valuable information to understand the stability and mechanism of PaaX and pave the way for further analysis of other regulators with similar structural configurations.

ChatGPT and most frequent urological diseases: analysing the quality of information and potential risks for patients.

PURPOSE: Artificial intelligence (AI) is a set of systems or combinations of algorithms, which mimic human intelligence. ChatGPT is software with artificial intelligence which was recently developed by OpenAI. One of its potential uses could be to consult the information about pathologies and treatments. Our objective was to assess the quality of the information provided by AI like ChatGPT and establish if it is a secure source of information for patients. METHODS: Questions about bladder cancer, prostate cancer, renal cancer, benign prostatic hypertrophy (BPH), and urinary stones were queried through ChatGPT 4.0. Two urologists analysed the responses provided by ChatGPT using DISCERN questionary and a brief instrument for evaluating the quality of informed consent documents. RESULTS: The overall information provided in all pathologies was well-balanced. In each pathology was explained its anatomical location, affected population and a description of the symptoms. It concluded with the established risk factors and possible treatment. All treatment answers had a moderate quality score with DISCERN (3 of 5 points). The answers about surgical options contain the recovery time, type of anaesthesia, and potential complications. After analysing all the responses related to each disease, all pathologies except BPH achieved a DISCERN score of 4. CONCLUSIONS: ChatGPT information should be used with caution since the chatbot does not disclose the sources of information and may contain bias even with simple questions related to the basics of urologic diseases.