Infections caused by multidrug‐resistant bacteria represent a significant and ever‐increasing cause of morbidity and mortality. There is thus an urgent need to develop efficient and well‐tolerated antibacterials targeting unique cellular processes. Numerous studies have led to the identification of new biological targets to fight bacterial resistance. Two‐component signal transduction systems are widely employed by bacteria to translate external and cellular signals into a cellular response. They are ubiquitous in bacteria, absent in the animal kingdom and are integrated into various virulence pathways. Several chemical series, including isothiazolidones, imidazolium salts, benzoxazines, salicylanilides, thiophenes, thiazolidiones, benzimidazoles, and other derivatives deduced by different approaches have been reported in the literature to have histidine kinase (HK) inhibitory activity. In this review, we report on the design and the synthesis of these HKs inhibitors and their potential to serve as antibacterial agents.
The rise of bacterial resistance to common clinical antibiotics is calling for alternative approaches to synthesize new antibacterial drugs with high environmental biodegradability. One such approach is the use of microwave-assisted synthesis, which is a powerful green synthetic technique used increasingly to accelerate organic reactions. To discover new antibacterial compounds, we report the efficient synthesis of nineteen thiophene derivatives, five furan derivatives, and two thiazole derivatives, using Suzuki-Miyaura cross-coupling by microwave irradiation. Microwave irradiation conditions have reduced the reaction time, increased the yield and this method uses less organic solvent compared to conventional heating. Several compounds showed broad antibacterial activity. One compound, in particular, demonstrated significant antibacterial activity against Streptococcus pyogenes with a minimal inhibitory concentration of 0.097 µg/mL and against Salmonella enterica with a minimal inhibitory concentration of 0.78 µg/mL. The biodegradability of two furan derivatives with the best antibacterial activities and their effects on environmental bacteria were studied using the closed bottle test. This test proved that the two compounds were readily biodegradable without toxic effects on environmental bacteria present in wastewater treatment plants. Therefore our data demonstrated not only green synthesis but also environmental benignity due to the biodegradability of the novel antibacterials, which is a very desirable feature.
NDM-1 (New-Delhi-Metallo-β-lactamase-1) is an enzyme developed by bacteria that is implicated in bacteria resistance to almost all known antibiotics. In this study, we deliver a new, curated NDM-1 bioactivities database, along with a set of unifying rules for managing different activity properties and inconsistencies. We define the activity classification problem in terms of Multiple Instance Learning, employing embeddings corresponding to molecular substructures and present an ensemble ranking and classification framework, relaying on a k-fold Cross Validation method employing a per fold hyper-parameter optimization procedure, showing promising generalization ability. The MIL paradigm displayed an improvement up to 45.7 %, in terms of Balanced Accuracy, in comparison to the classical Machine Learning paradigm. Moreover, we investigate different compact molecular representations, based on atomic or bi-atomic substructures. Finally, we scanned the Drugbank for strongly active compounds and we present the top-15 ranked compounds.
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