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The increasing emergence of drug-resistance among mycobacteria represents a serious global health threat, requiring novel and effective therapeutic strategies. The lack of innovation in the drug discovery approach and/or in the combination of the therapeutic cocktail makes inevitable the onset of resistance also for the newly marketed drugs such as bedaquiline and delamanid. Therefore, different therapeutic tools are urgently required. Adjuvant therapies (AT), that is those approaches aimed at boosting the existing treatment, rather than replacing it with another, have gained increasing consideration in the antibacterial landfill. Efflux Inhibitors (EIs) represent the most studied example of such an approach, as they can slow down the emergence of resistance and have positive effects on the duration of the treatment. Working toward this direction, we have recently reported the biological characterization of N-(3,5-dichlorophenyl)-4,5-dihydronaphtho[1,2-d]thiazol-2-amine (compound 1), a 2-aminothiazole derivative remarkably affecting Mycobacterium tuberculosis energetics. Despite the encouraging overall activity (MIC = 16 µg/mL, RFF = 3.29), this compound poses several medicinal chemistry challenges concerning its toxicity and drug-likeness. Here we present a Structure-Activity Relationships around compound 1, with the disclosure of some derivatives with balanced efflux inhibitory characteristics, tolerable toxicity and drug-like physicochemical features. [ABSTRACT FROM AUTHOR]

An ever-increasing demand for novel antimicrobials to treat life-threatening infections caused by the global spread of multidrug-resistant bacterial pathogens stands in stark contrast to the current level of investment in their development, particularly in the fields of natural-product-derived and synthetic small molecules. New agents displaying innovative chemistry and modes of action are desperately needed worldwide to tackle the public health menace posed by antimicrobial resistance. Here, our consortium presents a strategic blueprint to substantially improve our ability to discover and develop new antibiotics. We propose both short-term and long-term solutions to overcome the most urgent limitations in the various sectors of research and funding, aiming to bridge the gap between academic, industrial and political stakeholders, and to unite interdisciplinary expertise in order to efficiently fuel the translational pipeline for the benefit of future generations., (© 2021. Springer Nature Limited.)