Using computers to ESKAPE the antibiotic resistance crisis.

Since the discovery of penicillin, the development and use of antibiotics have promoted safe and effective control of bacterial infections. However, the number of antibiotic-resistance cases has been ever increasing over time. Thus, the drug discovery process demands fast, efficient and cost-effective alternative approaches for developing lead candidates with outstanding performance. Computational approaches are appealing techniques to develop lead candidates in an in silico fashion. In this review, we provide an overview of the implementation of current in silico state-of-the-art techniques, including machine learning (ML) and deep learning (DL), in drug discovery. We also discuss the development of quantum computing and its potential benefits for antibiotics research and current bottlenecks that limit computational drug discovery advancement.

Tandem anaerobic-aerobic degradation of ranitidine, diclofenac, and simvastatin in domestic sewage.

There is a consensus among scientists that domestic sewage treatment plants are the main sources of drugs entry into the aquatic environment. Therefore, this work studies the biodegradation of the drugs ranitidine (RNT), diclofenac (DCF), and simvastatin (SVT) (50 µg L-1, each), in real domestic sewage, using a continuous anaerobic-aerobic reactor with immobilized biomass and an anaerobic batch reactor. The continuous anaerobic-aerobic reactor was operated for 6 months with hydraulic retention time (HRT) of 8 h. The initial degradation rates and the maximum oxidation capacities (MOC) of the system were estimated, achieving 90, 72, and 62% removals and 100, 93, and 72% of MOC for RNT, DCF and SVT, respectively, as well as 71% removal of soluble chemical oxygen demand (COD). RNT was degraded throughout the reactor, while DCF was degraded mainly in the two anaerobic chambers and SVT in the first anaerobic chamber. Anaerobic batches were used for the identification of biodegradation by-products (2,6-dichloro-N-(2-methylphenyl) aniline and simvastatin acid), the evaluation of the specific methanogenic activity (SMA) inhibition, and the estimation of acute and chronic ecotoxicities using the ECOSAR 1.11 software. The present study showed that, even at environmental concentrations, RNT, DCF, and SVT were capable of inhibiting the SMA. Lipophilicities dictated the behavior of those three drugs. The greater their lipophilicities, the greater the SMA inhibition and their ecotoxicity.

Aquatic toxicity of dyes before and after photo-Fenton treatment.

This study evaluated the ecotoxicity of five dyes to freshwater organisms before and during their photo-Fenton degradation. EC50 (48h) of the five tested dyes ranged from of 6.9 to >1000mgL(-1) for Daphnia similis. In the chronic tests IC50 (72h) varied from 65 to >100mgL(-1) for Pseudokirchneriella subcapitata and IC50 (8 days) from 0.5 to 410mgL(-1) for Ceriodaphnia dubia. Toxicity tests revealed that although the applied treatment was effective for decolorization of the dye, the partial mineralization may be responsible for the presence of degradation products which can be either more toxic than the original dye, as is the case of Vat Green 3 and Reactive Black 5, lead to initially toxic products which may be further degraded to non toxic products (acid Orange 7 and Food Red 17), or generate non toxic products as in the case of Food Yellow 3. The results highlighted the importance of assessing both acute and chronic toxicity tests of treated sample before effluent discharge.

Cardiorespiratory, sedative and antinociceptive effects of dexmedetomidine alone or in combination with methadone, morphine or tramadol in dogs.

OBJECTIVE: To evaluate the cardiorespiratory, sedative and antinociceptive effects of dexmedetomidine alone or in combination with methadone, morphine or tramadol in dogs. STUDY DESIGN: Experimental, blinded, randomized, crossover study. ANIMALS: Six mixed breed dogs (two males and four females) weighing 10 ± 4 kg. METHODS: The animals were randomly divided into four treatments: D (10 µg kg(-1) of dexmedetomidine), DM (dexmedetomidine 10 µg kg(-1) and methadone 0.5 mg kg(-1)); DMO (dexmedetomidine 10 µg kg(-1) and morphine 0.5 mg kg(-1)), and DT (dexmedetomidine 10 µg kg(-1) and tramadol 2 mg kg(-1)). The combinations were administered intramuscularly in all treatments. The variables evaluated were heart rate (HR), respiratory rate (f(R)), rectal temperature (RT), systolic arterial pressure (SAP), sedation scale and pedal withdrawal reflex. These variables were measured at T0 (immediately before the administration of the protocol) and every 15 minutes thereafter until T105. RESULTS: A decrease in HR and f(R) occurred in all the treatments compared with T0, but no significant difference was observed between the treatments. The RT decreased from T45 onward in all the treatments. The SAP did not show a difference between the treatments, but in the DT treatment, the SAP was lower at T30 and T45 compared with T0. The D treatment had lower scores of sedation at T15 to T75 compared with the other treatments, and the DMO and DM treatments showed higher scores at T60 and T75 compared with DT. CONCLUSIONS AND CLINICAL RELEVANCE: The treatments with morphine and methadone added to the dexmedetomidine showed higher sedation scores than the control treatment and the treatment with tramadol added to the dexmedetomidine showed no relevant differences in any of the variables evaluated in the study.